EP2797597B1 - Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation - Google Patents
Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation Download PDFInfo
- Publication number
- EP2797597B1 EP2797597B1 EP12862096.0A EP12862096A EP2797597B1 EP 2797597 B1 EP2797597 B1 EP 2797597B1 EP 12862096 A EP12862096 A EP 12862096A EP 2797597 B1 EP2797597 B1 EP 2797597B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methoxy
- pyridin
- methyl
- pyrazol
- methoxyisonicotinaldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 heteroaryl aldehyde compounds Chemical class 0.000 title claims description 100
- 238000000034 method Methods 0.000 title claims description 46
- 230000000287 tissue oxygenation Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 219
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 79
- 229910052702 rhenium Inorganic materials 0.000 claims description 60
- 125000001072 heteroaryl group Chemical group 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 47
- 229910052760 oxygen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- KOHRPFLLTVVPID-UHFFFAOYSA-N 5-[(2-bromopyridin-3-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1Br KOHRPFLLTVVPID-UHFFFAOYSA-N 0.000 claims description 11
- 206010021143 Hypoxia Diseases 0.000 claims description 9
- YNTCMABHIDTLLK-UHFFFAOYSA-N 5-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-3-carboxylic acid Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C(O)=O)=C1 YNTCMABHIDTLLK-UHFFFAOYSA-N 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 208000007056 sickle cell anemia Diseases 0.000 claims description 8
- ZXJAECPCJLOCIF-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-[[2-(2-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OCCOC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C ZXJAECPCJLOCIF-UHFFFAOYSA-N 0.000 claims description 7
- GAEJJNBICDATLS-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C(C)C GAEJJNBICDATLS-UHFFFAOYSA-N 0.000 claims description 7
- UTVYKQIAACPLMS-UHFFFAOYSA-N 2-methoxy-5-[[2-(4-methyl-1h-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=C(C)C=NN1 UTVYKQIAACPLMS-UHFFFAOYSA-N 0.000 claims description 7
- ABWPGSUCALAYMA-UHFFFAOYSA-N 2-methoxy-5-[[2-(4-methyl-2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=C(C)C=NN1C(C)C ABWPGSUCALAYMA-UHFFFAOYSA-N 0.000 claims description 7
- XSXGYUKSWKGACV-UHFFFAOYSA-N 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN2C1=NC=C2 XSXGYUKSWKGACV-UHFFFAOYSA-N 0.000 claims description 7
- VYVMOYLAPYISCR-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(COC=2C(=CC=NC=2)C=O)=N1 VYVMOYLAPYISCR-UHFFFAOYSA-N 0.000 claims description 7
- RPPAINHSZZBTDE-UHFFFAOYSA-N 8-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]imidazo[1,2-a]pyridine-6-carboxamide Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(C(N)=O)=CN2C1=NC=C2 RPPAINHSZZBTDE-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- MYSFYOLFRVYQNE-UHFFFAOYSA-N 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC(F)F)=CC(C=O)=C1OCC1=CC=CN2C1=NC=C2 MYSFYOLFRVYQNE-UHFFFAOYSA-N 0.000 claims description 6
- ZWCJGVRJEUMHGO-UHFFFAOYSA-N 2-[5-[3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-1-yl]acetic acid Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CC(O)=O ZWCJGVRJEUMHGO-UHFFFAOYSA-N 0.000 claims description 6
- NBNBZNIPDOFXHK-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C NBNBZNIPDOFXHK-UHFFFAOYSA-N 0.000 claims description 6
- JKWFUQVXDRBZKL-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-propan-2-yl-1,2,4-triazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=NC=NN1C(C)C JKWFUQVXDRBZKL-UHFFFAOYSA-N 0.000 claims description 6
- YUXFLUOAODGQAA-UHFFFAOYSA-N 2-methoxy-5-[[2-(2h-tetrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=NNN=N1 YUXFLUOAODGQAA-UHFFFAOYSA-N 0.000 claims description 6
- DBPIMLLNZKEVFU-UHFFFAOYSA-N 2-methoxy-5-[[3-(1h-pyrazol-5-yl)isoquinolin-4-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C(C=2NN=CC=2)N=CC2=CC=CC=C12 DBPIMLLNZKEVFU-UHFFFAOYSA-N 0.000 claims description 6
- OSGQKCAQHBQXKX-UHFFFAOYSA-N 2-methoxy-5-[[3-(2-propan-2-ylpyrazol-3-yl)pyrazin-2-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=NC=CN=C1C1=CC=NN1C(C)C OSGQKCAQHBQXKX-UHFFFAOYSA-N 0.000 claims description 6
- OZBWADQFFHIYSC-UHFFFAOYSA-N 2-methoxy-5-[[3-(2-propan-2-ylpyrazol-3-yl)pyridin-4-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC=C1C1=CC=NN1C(C)C OZBWADQFFHIYSC-UHFFFAOYSA-N 0.000 claims description 6
- LLOJJCBSSKDQEM-UHFFFAOYSA-N 3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]benzoic acid Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CC(C(O)=O)=C1 LLOJJCBSSKDQEM-UHFFFAOYSA-N 0.000 claims description 6
- SDFFHFLIUGEIHB-UHFFFAOYSA-N 3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-2-carbonitrile Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C#N SDFFHFLIUGEIHB-UHFFFAOYSA-N 0.000 claims description 6
- YEMAUMAROXWWLQ-UHFFFAOYSA-N 3-[3-[3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-1-yl]propanoic acid Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=NN(CCC(O)=O)C=C1 YEMAUMAROXWWLQ-UHFFFAOYSA-N 0.000 claims description 6
- JPZCXANSBYJVHF-UHFFFAOYSA-N 3-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CN=CC(O)=C1C=O JPZCXANSBYJVHF-UHFFFAOYSA-N 0.000 claims description 6
- YTOAFICYALDHSA-UHFFFAOYSA-N 3-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound COC1=CN=CC(OCC=2C(=NC=CC=2)C=2N(N=CC=2)C(C)C)=C1C=O YTOAFICYALDHSA-UHFFFAOYSA-N 0.000 claims description 6
- ZHKMBZWWWIDMBS-UHFFFAOYSA-N 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OCCOC)=CC(C=O)=C1OCC1=CC=CN2C1=NC=C2 ZHKMBZWWWIDMBS-UHFFFAOYSA-N 0.000 claims description 6
- DXCYMCKMJKVTRF-UHFFFAOYSA-N 5-[[2-(2-hydroxypropan-2-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C(C)(C)O DXCYMCKMJKVTRF-UHFFFAOYSA-N 0.000 claims description 6
- NRKOGBVKZUYCIH-UHFFFAOYSA-N 5-[[2-[2-(2-hydroxyethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CCO NRKOGBVKZUYCIH-UHFFFAOYSA-N 0.000 claims description 6
- XQXAUIDUZVLMJN-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]-n-methylsulfonylpyridine-3-carboxamide Chemical compound N1=CC(C(=O)NS(=O)(=O)C)=CC=C1COC1=CN=CC=C1C=O XQXAUIDUZVLMJN-UHFFFAOYSA-N 0.000 claims description 6
- LGCAFAIFMIUXNI-UHFFFAOYSA-N 6-methyl-3-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-2-carbaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=C(C)N=C1C=O LGCAFAIFMIUXNI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 6
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- HMGCCDCLKQOPFK-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OCCOC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C(C)C HMGCCDCLKQOPFK-UHFFFAOYSA-N 0.000 claims description 5
- PZZLVMOIACIZFO-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OCCOC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CC(F)(F)F PZZLVMOIACIZFO-UHFFFAOYSA-N 0.000 claims description 5
- IGVYVZCZWQCNHJ-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OCCOC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CCC(F)(F)F IGVYVZCZWQCNHJ-UHFFFAOYSA-N 0.000 claims description 5
- OOEBCLVPIPYYFK-UHFFFAOYSA-N 2-(difluoromethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CN=C(OC(F)F)C=C1C=O OOEBCLVPIPYYFK-UHFFFAOYSA-N 0.000 claims description 5
- OJWDCGFHDWFEKG-UHFFFAOYSA-N 2-methoxy-5-(pyridin-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC=C1 OJWDCGFHDWFEKG-UHFFFAOYSA-N 0.000 claims description 5
- POWIGENQVSKYHG-UHFFFAOYSA-N 2-methoxy-5-(quinolin-2-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(C=CC=C2)C2=N1 POWIGENQVSKYHG-UHFFFAOYSA-N 0.000 claims description 5
- DOWABJMXQYOYHS-UHFFFAOYSA-N 2-methoxy-5-(quinolin-3-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=C(C=CC=C2)C2=C1 DOWABJMXQYOYHS-UHFFFAOYSA-N 0.000 claims description 5
- ZYOUKBOUSOXQBW-UHFFFAOYSA-N 2-methoxy-5-(quinolin-5-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CC2=NC=CC=C12 ZYOUKBOUSOXQBW-UHFFFAOYSA-N 0.000 claims description 5
- SPIHMKDRPDSOML-UHFFFAOYSA-N 2-methoxy-5-[(1-methylindazol-4-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CC2=C1C=NN2C SPIHMKDRPDSOML-UHFFFAOYSA-N 0.000 claims description 5
- JVPKONRALACHPL-UHFFFAOYSA-N 2-methoxy-5-[(2-phenylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=CC=C1 JVPKONRALACHPL-UHFFFAOYSA-N 0.000 claims description 5
- ZINDRZKXBJAPGR-UHFFFAOYSA-N 2-methoxy-5-[(2-pyrazol-1-ylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1N1N=CC=C1 ZINDRZKXBJAPGR-UHFFFAOYSA-N 0.000 claims description 5
- UQQCXPTXXSFYEC-UHFFFAOYSA-N 2-methoxy-5-[(2-pyridin-3-ylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=CN=C1 UQQCXPTXXSFYEC-UHFFFAOYSA-N 0.000 claims description 5
- ANDRSMSEUBWDCW-UHFFFAOYSA-N 2-methoxy-5-[(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN2C1=NN=C2C ANDRSMSEUBWDCW-UHFFFAOYSA-N 0.000 claims description 5
- SODIGTHQSJCJDY-UHFFFAOYSA-N 2-methoxy-5-[(5-methylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C)=C1 SODIGTHQSJCJDY-UHFFFAOYSA-N 0.000 claims description 5
- FVYWSWNRUKFXMY-UHFFFAOYSA-N 2-methoxy-5-[[2-(1-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=NN(C)C=C1 FVYWSWNRUKFXMY-UHFFFAOYSA-N 0.000 claims description 5
- REUKYGSZQRYKGY-UHFFFAOYSA-N 2-methoxy-5-[[2-(1h-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1 REUKYGSZQRYKGY-UHFFFAOYSA-N 0.000 claims description 5
- JIXFXTWWPLQINM-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-methoxypyridin-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=CN=C1OC JIXFXTWWPLQINM-UHFFFAOYSA-N 0.000 claims description 5
- IDGJXYZSGYFNCP-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-methylphenyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=CC=C1C IDGJXYZSGYFNCP-UHFFFAOYSA-N 0.000 claims description 5
- RDIBINYHGRQOQV-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-propylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound CCCN1N=CC=C1C1=NC=CC=C1COC1=CN=C(OC)C=C1C=O RDIBINYHGRQOQV-UHFFFAOYSA-N 0.000 claims description 5
- UIARAZBAXLMSGV-UHFFFAOYSA-N 2-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CC(F)(F)F UIARAZBAXLMSGV-UHFFFAOYSA-N 0.000 claims description 5
- VHVOTWWVKLBMDA-UHFFFAOYSA-N 2-methoxy-5-[[2-[2-(2-methoxyethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound COCCN1N=CC=C1C1=NC=CC=C1COC1=CN=C(OC)C=C1C=O VHVOTWWVKLBMDA-UHFFFAOYSA-N 0.000 claims description 5
- YXQOVIPZAIRFIL-UHFFFAOYSA-N 2-methoxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CCC(F)(F)F YXQOVIPZAIRFIL-UHFFFAOYSA-N 0.000 claims description 5
- GBHNRVNQMBLNHE-UHFFFAOYSA-N 2-methoxy-5-[[5-(2-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C=2N(N=CC=2)C)=C1 GBHNRVNQMBLNHE-UHFFFAOYSA-N 0.000 claims description 5
- ABHUZLJQDQZFBE-UHFFFAOYSA-N 2-methyl-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(C)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CC(F)(F)F ABHUZLJQDQZFBE-UHFFFAOYSA-N 0.000 claims description 5
- KPJQOTUFYUTBKG-UHFFFAOYSA-N 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CN2C1=NC=C2 KPJQOTUFYUTBKG-UHFFFAOYSA-N 0.000 claims description 5
- WVHVSOWBYFYCLU-UHFFFAOYSA-N 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=CC=CN2C1=NC=C2 WVHVSOWBYFYCLU-UHFFFAOYSA-N 0.000 claims description 5
- PWPBQWXAXGBEHS-UHFFFAOYSA-N 3-(isoquinolin-1-ylmethoxy)-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=NC=CC2=CC=CC=C12 PWPBQWXAXGBEHS-UHFFFAOYSA-N 0.000 claims description 5
- BIWHAJXGMDRRIW-UHFFFAOYSA-N 3-[(2-formyl-6-methylpyridin-3-yl)oxymethyl]benzoic acid Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC(C(O)=O)=C1 BIWHAJXGMDRRIW-UHFFFAOYSA-N 0.000 claims description 5
- WJWFEEBFCHNMSE-UHFFFAOYSA-N 3-[5-[3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-1-yl]propanoic acid Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CCC(O)=O WJWFEEBFCHNMSE-UHFFFAOYSA-N 0.000 claims description 5
- IWNCTGOVAXHULU-UHFFFAOYSA-N 3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound FC(F)(F)CN1N=CC=C1C1=NC=CC=C1COC1=CN=CC=C1C=O IWNCTGOVAXHULU-UHFFFAOYSA-N 0.000 claims description 5
- XWVLJSYGQLMBHJ-UHFFFAOYSA-N 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CN=CC(Cl)=C1C=O XWVLJSYGQLMBHJ-UHFFFAOYSA-N 0.000 claims description 5
- IYZJDCHICKDMSH-UHFFFAOYSA-N 3-hydroxy-5-phenylmethoxypyridine-4-carbaldehyde Chemical compound OC1=CN=CC(OCC=2C=CC=CC=2)=C1C=O IYZJDCHICKDMSH-UHFFFAOYSA-N 0.000 claims description 5
- DWMMOSWYLGVSRN-UHFFFAOYSA-N 4-[(2-formyl-6-methylpyridin-3-yl)oxymethyl]benzoic acid Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=C(C(O)=O)C=C1 DWMMOSWYLGVSRN-UHFFFAOYSA-N 0.000 claims description 5
- LVZQEZRZGIBWOY-UHFFFAOYSA-N 5-(1,3-benzoxazol-4-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CC2=C1N=CO2 LVZQEZRZGIBWOY-UHFFFAOYSA-N 0.000 claims description 5
- YIUUVBBWUJWUQZ-UHFFFAOYSA-N 5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN2C1=CN=C2 YIUUVBBWUJWUQZ-UHFFFAOYSA-N 0.000 claims description 5
- MGPGATBOAHNXJS-UHFFFAOYSA-N 5-(isoquinolin-1-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=NC=CC2=CC=CC=C12 MGPGATBOAHNXJS-UHFFFAOYSA-N 0.000 claims description 5
- YPUVLFWQYYJMBE-UHFFFAOYSA-N 5-[(5-bromopyridin-3-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(Br)=C1 YPUVLFWQYYJMBE-UHFFFAOYSA-N 0.000 claims description 5
- QXPXCTYSNZUNAN-UHFFFAOYSA-N 5-[[2-(1,5-dimethylpyrazol-4-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=C(C)N(C)N=C1 QXPXCTYSNZUNAN-UHFFFAOYSA-N 0.000 claims description 5
- RYQOAZACLHROFP-UHFFFAOYSA-N 5-[[2-(2-cyclobutylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C1CCC1 RYQOAZACLHROFP-UHFFFAOYSA-N 0.000 claims description 5
- XYPKMXLDNCBZEX-UHFFFAOYSA-N 5-[[2-(2-cyclohexylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C1CCCCC1 XYPKMXLDNCBZEX-UHFFFAOYSA-N 0.000 claims description 5
- GZOWVZCEYNOHPR-UHFFFAOYSA-N 5-[[2-(2-cyclopentylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C1CCCC1 GZOWVZCEYNOHPR-UHFFFAOYSA-N 0.000 claims description 5
- JFXJAKUAFBZTCO-UHFFFAOYSA-N 5-[[2-(2-ethylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound CCN1N=CC=C1C1=NC=CC=C1COC1=CN=C(OC)C=C1C=O JFXJAKUAFBZTCO-UHFFFAOYSA-N 0.000 claims description 5
- FCLTTYCAPBPJJK-UHFFFAOYSA-N 5-[[2-(4-methyl-1h-pyrazol-5-yl)pyridin-3-yl]methoxy]-2-oxo-1h-pyridine-4-carbaldehyde Chemical compound C1=NNC(C=2C(=CC=CN=2)COC=2C(=CC(=O)NC=2)C=O)=C1C FCLTTYCAPBPJJK-UHFFFAOYSA-N 0.000 claims description 5
- CHBWYBWJDWKHCG-UHFFFAOYSA-N 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CC(F)F CHBWYBWJDWKHCG-UHFFFAOYSA-N 0.000 claims description 5
- IBCRAUYTFDPKLH-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyridine-3-carboxylic acid;hydrochloride Chemical compound Cl.N1=CC(C(=O)O)=CC=C1COC1=CN=CC=C1C=O IBCRAUYTFDPKLH-UHFFFAOYSA-N 0.000 claims description 5
- JKSWYGJADUWXNB-UHFFFAOYSA-N 6-methyl-3-(1,5-naphthyridin-4-ylmethoxy)pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=NC2=CC=CN=C12 JKSWYGJADUWXNB-UHFFFAOYSA-N 0.000 claims description 5
- AXJXUPZZDLGUJN-UHFFFAOYSA-N 6-methyl-3-(quinolin-5-ylmethoxy)pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC2=NC=CC=C12 AXJXUPZZDLGUJN-UHFFFAOYSA-N 0.000 claims description 5
- DOECFWSNSFXUTQ-UHFFFAOYSA-N 6-methyl-3-[(1-methylindazol-7-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC2=C1N(C)N=C2 DOECFWSNSFXUTQ-UHFFFAOYSA-N 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 5
- 125000005872 benzooxazolyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- NPMXBUKFXRPNMD-UHFFFAOYSA-N methyl 2-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]imidazo[1,2-a]pyridine-8-carboxylate Chemical compound N1=C2C(C(=O)OC)=CC=CN2C=C1COC1=CN=C(OC)C=C1C=O NPMXBUKFXRPNMD-UHFFFAOYSA-N 0.000 claims description 5
- PUAJQOLVZAECPN-UHFFFAOYSA-N methyl 3-[(2-formyl-6-methylpyridin-3-yl)oxymethyl]benzoate Chemical compound COC(=O)C1=CC=CC(COC=2C(=NC(C)=CC=2)C=O)=C1 PUAJQOLVZAECPN-UHFFFAOYSA-N 0.000 claims description 5
- QPACXSYLBFDYAU-UHFFFAOYSA-N methyl 3-[5-[3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-1-yl]propanoate Chemical compound COC(=O)CCN1N=CC=C1C1=NC=CC=C1COC1=CN=C(OC)C=C1C=O QPACXSYLBFDYAU-UHFFFAOYSA-N 0.000 claims description 5
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- JWVDDKKOPIMXMN-UHFFFAOYSA-N 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1OCC1=CC=CN2C1=NC=C2 JWVDDKKOPIMXMN-UHFFFAOYSA-N 0.000 claims description 4
- OPBQUVAQXMPATQ-UHFFFAOYSA-N 2-methoxy-5-[(2-methylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C OPBQUVAQXMPATQ-UHFFFAOYSA-N 0.000 claims description 4
- OIDJRBLHLWBVBH-UHFFFAOYSA-N 2-methoxy-5-[(6-methylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(C)N=C1 OIDJRBLHLWBVBH-UHFFFAOYSA-N 0.000 claims description 4
- MEEFGJFBKJOIPD-UHFFFAOYSA-N 2-methoxy-5-[[2-(3-methylpyrazol-1-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1N1N=C(C)C=C1 MEEFGJFBKJOIPD-UHFFFAOYSA-N 0.000 claims description 4
- SSPZEYPEYPTHPO-UHFFFAOYSA-N 2-methoxy-5-[[4-(1h-pyrazol-4-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC=C1C1=CNN=C1 SSPZEYPEYPTHPO-UHFFFAOYSA-N 0.000 claims description 4
- RVTCBYFMHUJDSC-UHFFFAOYSA-N 2-methoxy-5-[[6-(2h-tetrazol-5-yl)imidazo[1,2-a]pyridin-8-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(C2=NNN=N2)=CN2C1=NC=C2 RVTCBYFMHUJDSC-UHFFFAOYSA-N 0.000 claims description 4
- RVBJTGLFFOFCIG-UHFFFAOYSA-N 2-methyl-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(C)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1CCC(F)(F)F RVBJTGLFFOFCIG-UHFFFAOYSA-N 0.000 claims description 4
- IWIRBIDLKIKEQB-UHFFFAOYSA-N 3-[(2-formylpyridin-3-yl)oxymethyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(COC=2C(=NC=CC=2)C=O)=C1 IWIRBIDLKIKEQB-UHFFFAOYSA-N 0.000 claims description 4
- RFBWHXSNIQLUQR-UHFFFAOYSA-N 3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-2-carboxylic acid Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C(O)=O RFBWHXSNIQLUQR-UHFFFAOYSA-N 0.000 claims description 4
- PMJFYTUORXDSFP-UHFFFAOYSA-N 3-[(4-formylpyridin-3-yl)oxymethyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(COC=2C(=CC=NC=2)C=O)=C1 PMJFYTUORXDSFP-UHFFFAOYSA-N 0.000 claims description 4
- NKXRMOGTDVRQIK-UHFFFAOYSA-N 3-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-2-carbaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CN=C1C=O NKXRMOGTDVRQIK-UHFFFAOYSA-N 0.000 claims description 4
- IIDCJUVYDQAVDU-UHFFFAOYSA-N 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound FC(F)(F)CCN1N=CC=C1C1=NC=CC=C1COC1=CN=CC=C1C=O IIDCJUVYDQAVDU-UHFFFAOYSA-N 0.000 claims description 4
- JKNMMSLTNDZJFI-UHFFFAOYSA-N 3-chloro-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound FC(F)(F)CCN1N=CC=C1C1=NC=CC=C1COC1=CN=CC(Cl)=C1C=O JKNMMSLTNDZJFI-UHFFFAOYSA-N 0.000 claims description 4
- NQSWIAJEYIFANM-UHFFFAOYSA-N 3-methyl-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CN=CC(C)=C1C=O NQSWIAJEYIFANM-UHFFFAOYSA-N 0.000 claims description 4
- SOPSDUKXZQPYCT-UHFFFAOYSA-N 3-methyl-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound CC1=CN=CC(OCC=2C(=NC=CC=2)C=2N(N=CC=2)CC(F)(F)F)=C1C=O SOPSDUKXZQPYCT-UHFFFAOYSA-N 0.000 claims description 4
- LGULLRQFNQOXFJ-UHFFFAOYSA-N 4-[(2-formylpyridin-3-yl)oxymethyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1COC1=CC=CN=C1C=O LGULLRQFNQOXFJ-UHFFFAOYSA-N 0.000 claims description 4
- JBZACTRWZAYQQW-UHFFFAOYSA-N 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1h-pyridine-4-carbaldehyde Chemical compound O=CC1=CC(=O)NC=C1OCC1=CC=CN2C1=NC=C2 JBZACTRWZAYQQW-UHFFFAOYSA-N 0.000 claims description 4
- QWIXOMYGRZKIHB-UHFFFAOYSA-N 5-[(2-chloroquinolin-3-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC2=CC=CC=C2N=C1Cl QWIXOMYGRZKIHB-UHFFFAOYSA-N 0.000 claims description 4
- UAFSMOKZCTYBKD-UHFFFAOYSA-N 5-[(3-bromopyridin-4-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC=C1Br UAFSMOKZCTYBKD-UHFFFAOYSA-N 0.000 claims description 4
- MDMKMMYYLANXAU-UHFFFAOYSA-N 5-[(6-bromoimidazo[1,2-a]pyridin-8-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(Br)=CN2C1=NC=C2 MDMKMMYYLANXAU-UHFFFAOYSA-N 0.000 claims description 4
- XTTZLOVKLMHABE-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyridine-3-carbonitrile;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.O=CC1=CC=NC=C1OCC1=CC=C(C#N)C=N1 XTTZLOVKLMHABE-UHFFFAOYSA-N 0.000 claims description 4
- JZCPLPDEGAVOEZ-UHFFFAOYSA-N 6-methyl-3-[(1-methylindazol-6-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=C(C=NN2C)C2=C1 JZCPLPDEGAVOEZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- IXNQVTHZJDFCLV-UHFFFAOYSA-N methyl 3-[(4-formylpyridin-3-yl)oxymethyl]benzoate Chemical compound COC(=O)C1=CC=CC(COC=2C(=CC=NC=2)C=O)=C1 IXNQVTHZJDFCLV-UHFFFAOYSA-N 0.000 claims description 4
- HPQROVNUKCNFHE-UHFFFAOYSA-N methyl 5-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=CC(COC=2C(=CC(OC)=NC=2)C=O)=C1 HPQROVNUKCNFHE-UHFFFAOYSA-N 0.000 claims description 4
- KZCDESOAOXNWJM-UHFFFAOYSA-N tert-butyl 4-[(2-formyl-6-methylpyridin-3-yl)oxymethyl]indazole-1-carboxylate Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC2=C1C=NN2C(=O)OC(C)(C)C KZCDESOAOXNWJM-UHFFFAOYSA-N 0.000 claims description 4
- ZLZCNZORABGXAF-UHFFFAOYSA-N 2-methoxy-5-(1,3-oxazol-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=COC=N1 ZLZCNZORABGXAF-UHFFFAOYSA-N 0.000 claims description 3
- KOYCEEBLFWMGLR-UHFFFAOYSA-N 2-methoxy-5-(1,3-oxazol-5-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CO1 KOYCEEBLFWMGLR-UHFFFAOYSA-N 0.000 claims description 3
- LNIVEQRJNHAXOD-UHFFFAOYSA-N 2-methoxy-5-(1,5-naphthyridin-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC2=CC=CN=C12 LNIVEQRJNHAXOD-UHFFFAOYSA-N 0.000 claims description 3
- STVRFSQYLBAELK-UHFFFAOYSA-N 2-methoxy-5-(1h-1,2,4-triazol-5-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=NN=CN1 STVRFSQYLBAELK-UHFFFAOYSA-N 0.000 claims description 3
- LKPRDHFLXATBQJ-UHFFFAOYSA-N 2-methoxy-5-(1h-pyrazol-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CNN=C1 LKPRDHFLXATBQJ-UHFFFAOYSA-N 0.000 claims description 3
- CDHFAYZADKNUNF-UHFFFAOYSA-N 2-methoxy-5-(1h-pyrazol-5-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NN1 CDHFAYZADKNUNF-UHFFFAOYSA-N 0.000 claims description 3
- NGRSYGUMPSRDBC-UHFFFAOYSA-N 2-methoxy-5-(1h-pyrazolo[3,4-b]pyridin-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC2=C1C=NN2 NGRSYGUMPSRDBC-UHFFFAOYSA-N 0.000 claims description 3
- ZKADQQUMOAHSPD-UHFFFAOYSA-N 2-methoxy-5-(2h-tetrazol-5-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=NN=NN1 ZKADQQUMOAHSPD-UHFFFAOYSA-N 0.000 claims description 3
- WCMFWGNIPTXRQH-UHFFFAOYSA-N 2-methoxy-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C2CNCCN2N=C1 WCMFWGNIPTXRQH-UHFFFAOYSA-N 0.000 claims description 3
- SGZOJBQTINQDNZ-UHFFFAOYSA-N 2-methoxy-5-(pyridin-3-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1 SGZOJBQTINQDNZ-UHFFFAOYSA-N 0.000 claims description 3
- AVGHPZWAHYTRKA-UHFFFAOYSA-N 2-methoxy-5-(quinoxalin-2-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=C(C=CC=C2)C2=N1 AVGHPZWAHYTRKA-UHFFFAOYSA-N 0.000 claims description 3
- DXOZRWOAWJNZNN-UHFFFAOYSA-N 2-methoxy-5-[(1-methyl-2-oxopyridin-4-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(=O)N(C)C=C1 DXOZRWOAWJNZNN-UHFFFAOYSA-N 0.000 claims description 3
- VTZHDFNUPKYDCP-UHFFFAOYSA-N 2-methoxy-5-[(1-methylindazol-5-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(N(C)N=C2)C2=C1 VTZHDFNUPKYDCP-UHFFFAOYSA-N 0.000 claims description 3
- ZVPRYBYTVAPADX-UHFFFAOYSA-N 2-methoxy-5-[(1-methylindazol-7-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CC2=C1N(C)N=C2 ZVPRYBYTVAPADX-UHFFFAOYSA-N 0.000 claims description 3
- VRSRVAWUSSSVHY-UHFFFAOYSA-N 2-methoxy-5-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=C(N(C)N=C2)C2=C1 VRSRVAWUSSSVHY-UHFFFAOYSA-N 0.000 claims description 3
- JQOIKMWZZCNXFK-UHFFFAOYSA-N 2-methoxy-5-[(2-oxo-1h-pyridin-4-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(=O)NC=C1 JQOIKMWZZCNXFK-UHFFFAOYSA-N 0.000 claims description 3
- KPNLXHGSKASUSC-UHFFFAOYSA-N 2-methoxy-5-[(3-methylpyridin-4-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC=C1C KPNLXHGSKASUSC-UHFFFAOYSA-N 0.000 claims description 3
- JMQKLVRDLTVZEA-UHFFFAOYSA-N 2-methoxy-5-[(4-methylpyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC=C1C JMQKLVRDLTVZEA-UHFFFAOYSA-N 0.000 claims description 3
- QAFLZIBDNVYIEI-UHFFFAOYSA-N 2-methoxy-5-[(6-oxo-1h-pyridin-3-yl)methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CNC(=O)C=C1 QAFLZIBDNVYIEI-UHFFFAOYSA-N 0.000 claims description 3
- PTGJJSQKGUMNFX-UHFFFAOYSA-N 2-methoxy-5-[[2-(1-methylpyrazol-4-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CN(C)N=C1 PTGJJSQKGUMNFX-UHFFFAOYSA-N 0.000 claims description 3
- DTRZPWRUHMGUJO-UHFFFAOYSA-N 2-methoxy-5-[[2-(1h-pyrazol-4-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CNN=C1 DTRZPWRUHMGUJO-UHFFFAOYSA-N 0.000 claims description 3
- RHCBEXVMXLKLAG-UHFFFAOYSA-N 2-methoxy-5-[[2-(1h-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C2C=NC=CN2N=C1C1=CC=NN1 RHCBEXVMXLKLAG-UHFFFAOYSA-N 0.000 claims description 3
- ASWVBOFATVAMON-UHFFFAOYSA-N 2-methoxy-5-[[2-[4-(1h-pyrazol-5-yl)piperazin-1-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1N1CCN(C2=NNC=C2)CC1 ASWVBOFATVAMON-UHFFFAOYSA-N 0.000 claims description 3
- AYHPQRXIKFSQBZ-UHFFFAOYSA-N 2-methoxy-5-[[3-(1h-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C(C=2NN=CC=2)N2C=CC=CC2=N1 AYHPQRXIKFSQBZ-UHFFFAOYSA-N 0.000 claims description 3
- ICEMPQNGHVMHHF-UHFFFAOYSA-N 2-methoxy-5-[[4-(1h-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC=C1C1=CC=NN1 ICEMPQNGHVMHHF-UHFFFAOYSA-N 0.000 claims description 3
- MVYFZULSOHSKNB-UHFFFAOYSA-N 2-methoxy-5-[[5-(1-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C2=NN(C)C=C2)=C1 MVYFZULSOHSKNB-UHFFFAOYSA-N 0.000 claims description 3
- AANSHLONGOBZSZ-UHFFFAOYSA-N 2-methoxy-5-[[5-(1-methylpyrazol-4-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C2=CN(C)N=C2)=C1 AANSHLONGOBZSZ-UHFFFAOYSA-N 0.000 claims description 3
- MDDZLHDUFSCRSO-UHFFFAOYSA-N 2-methoxy-5-[[5-(1h-pyrazol-4-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C2=CNN=C2)=C1 MDDZLHDUFSCRSO-UHFFFAOYSA-N 0.000 claims description 3
- FXNVOFWRXXEWCP-UHFFFAOYSA-N 2-methoxy-5-[[5-(1h-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C=2NN=CC=2)=C1 FXNVOFWRXXEWCP-UHFFFAOYSA-N 0.000 claims description 3
- CLYPSYTUCWYMLM-UHFFFAOYSA-N 2-methoxy-5-[[5-(2h-tetrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C2=NNN=N2)=C1 CLYPSYTUCWYMLM-UHFFFAOYSA-N 0.000 claims description 3
- OHLGZLUKCWMYAJ-UHFFFAOYSA-N 2-methoxy-5-[[6-(1h-pyrazol-4-yl)imidazo[1,2-a]pyridin-8-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(C2=CNN=C2)=CN2C1=NC=C2 OHLGZLUKCWMYAJ-UHFFFAOYSA-N 0.000 claims description 3
- URJOMERNGWFDTQ-UHFFFAOYSA-N 2-methoxy-5-[[6-(1h-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN(C=C(C=C2)C3=NNC=C3)C2=N1 URJOMERNGWFDTQ-UHFFFAOYSA-N 0.000 claims description 3
- NEVSNIXLMFXSRK-UHFFFAOYSA-N 2-methoxy-5-[[6-(1h-pyrazol-5-yl)imidazo[1,2-a]pyridin-8-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(C=2NN=CC=2)=CN2C1=NC=C2 NEVSNIXLMFXSRK-UHFFFAOYSA-N 0.000 claims description 3
- VQFXMFYQINEBNU-UHFFFAOYSA-N 2-methoxy-5-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN(C=C(C=C2)C(F)(F)F)C2=N1 VQFXMFYQINEBNU-UHFFFAOYSA-N 0.000 claims description 3
- LRFJDTXMFGDMGF-UHFFFAOYSA-N 2-methoxy-5-[[6-(trifluoromethyl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(C(F)(F)F)N=C1 LRFJDTXMFGDMGF-UHFFFAOYSA-N 0.000 claims description 3
- VDSAYVVYGXZPKO-UHFFFAOYSA-N 2-methoxy-5-[[7-(1h-pyrazol-5-yl)imidazo[1,5-a]pyridin-8-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C(C2=NNC=C2)C=CN2C1=CN=C2 VDSAYVVYGXZPKO-UHFFFAOYSA-N 0.000 claims description 3
- XZHHYYBISLIEDY-UHFFFAOYSA-N 2-methoxy-5-[[8-(2-methylpyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN(C=CC=C2C=3N(N=CC=3)C)C2=N1 XZHHYYBISLIEDY-UHFFFAOYSA-N 0.000 claims description 3
- MUEHCEDSDQQDTF-UHFFFAOYSA-N 3-(1,3-benzoxazol-4-ylmethoxy)-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC2=C1N=CO2 MUEHCEDSDQQDTF-UHFFFAOYSA-N 0.000 claims description 3
- ZOUARSDCJUOJCP-UHFFFAOYSA-N 3-(1h-pyrazolo[3,4-b]pyridin-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=CC=NC2=C1C=NN2 ZOUARSDCJUOJCP-UHFFFAOYSA-N 0.000 claims description 3
- PBNHDQHPKOMSHT-UHFFFAOYSA-N 3-(imidazo[1,5-a]pyridin-8-ylmethoxy)-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CN2C1=CN=C2 PBNHDQHPKOMSHT-UHFFFAOYSA-N 0.000 claims description 3
- VLFBOKRYEFBGFX-UHFFFAOYSA-N 3-(imidazo[1,5-a]pyridin-8-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=CC=CN2C1=CN=C2 VLFBOKRYEFBGFX-UHFFFAOYSA-N 0.000 claims description 3
- YCXRKQBIINNPFW-UHFFFAOYSA-N 3-(isoquinolin-7-ylmethoxy)-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=C(C=CN=C2)C2=C1 YCXRKQBIINNPFW-UHFFFAOYSA-N 0.000 claims description 3
- YSNZRMFYCIANIS-UHFFFAOYSA-N 3-(pyridin-3-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=CC=CN=C1 YSNZRMFYCIANIS-UHFFFAOYSA-N 0.000 claims description 3
- HDTTUGIGNFKMJI-UHFFFAOYSA-N 3-[(1,3-dimethylpyrazolo[3,4-b]pyridin-4-yl)methoxy]-6-methylpyridine-2-carbaldehyde Chemical compound C=12C(C)=NN(C)C2=NC=CC=1COC1=CC=C(C)N=C1C=O HDTTUGIGNFKMJI-UHFFFAOYSA-N 0.000 claims description 3
- RQRTXNKISXSTMD-UHFFFAOYSA-N 3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyrazolo[1,5-a]pyrazine-2-carboxamide Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C2C=NC=CN2N=C1C(N)=O RQRTXNKISXSTMD-UHFFFAOYSA-N 0.000 claims description 3
- ZIBUDQZOWJUMEO-UHFFFAOYSA-N 3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-2-carboxamide Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C(N)=O ZIBUDQZOWJUMEO-UHFFFAOYSA-N 0.000 claims description 3
- GRLKDZXQIOBAMC-UHFFFAOYSA-N 4-(pyridin-3-ylmethoxy)pyridine-3-carbaldehyde Chemical compound O=CC1=CN=CC=C1OCC1=CC=CN=C1 GRLKDZXQIOBAMC-UHFFFAOYSA-N 0.000 claims description 3
- KIIRCIQLUNBKRH-UHFFFAOYSA-N 5-(1h-imidazol-2-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=NC=CN1 KIIRCIQLUNBKRH-UHFFFAOYSA-N 0.000 claims description 3
- CWOIXFQKOJHBSC-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CN1 CWOIXFQKOJHBSC-UHFFFAOYSA-N 0.000 claims description 3
- TZOCSPWHZMZQPF-UHFFFAOYSA-N 5-(1h-indazol-4-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CC2=C1C=NN2 TZOCSPWHZMZQPF-UHFFFAOYSA-N 0.000 claims description 3
- UWDVGDMEAZPIBL-UHFFFAOYSA-N 5-(1h-indazol-5-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(NN=C2)C2=C1 UWDVGDMEAZPIBL-UHFFFAOYSA-N 0.000 claims description 3
- PBCJZEVQJYQQOB-UHFFFAOYSA-N 5-(2-imidazo[1,2-a]pyridin-8-ylethyl)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1CCC1=CC=CN2C1=NC=C2 PBCJZEVQJYQQOB-UHFFFAOYSA-N 0.000 claims description 3
- KYTCVSRBDYHFPU-UHFFFAOYSA-N 5-(isoquinolin-7-ylmethoxy)-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(C=CN=C2)C2=C1 KYTCVSRBDYHFPU-UHFFFAOYSA-N 0.000 claims description 3
- HQVMJZPBJXJPOE-UHFFFAOYSA-N 5-[(1,3-dimethylpyrazolo[3,4-b]pyridin-4-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=NC2=C1C(C)=NN2C HQVMJZPBJXJPOE-UHFFFAOYSA-N 0.000 claims description 3
- BFJPODAYSDPUDK-UHFFFAOYSA-N 5-[(3-bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C(Br)N2C=CC=CC2=N1 BFJPODAYSDPUDK-UHFFFAOYSA-N 0.000 claims description 3
- OENMYIAAUHVNCE-UHFFFAOYSA-N 5-[(3-chloro-1-methylindazol-5-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(N(C)N=C2Cl)C2=C1 OENMYIAAUHVNCE-UHFFFAOYSA-N 0.000 claims description 3
- MRGJIPQNRPVRJM-UHFFFAOYSA-N 5-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-2-carbonitrile Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=C(C#N)N=C1 MRGJIPQNRPVRJM-UHFFFAOYSA-N 0.000 claims description 3
- BJKXVORFNZELJY-UHFFFAOYSA-N 5-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-3-carbonitrile Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C#N)=C1 BJKXVORFNZELJY-UHFFFAOYSA-N 0.000 claims description 3
- KLGKKNKEDZBSNI-UHFFFAOYSA-N 5-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-3-carboxamide Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN=CC(C(N)=O)=C1 KLGKKNKEDZBSNI-UHFFFAOYSA-N 0.000 claims description 3
- RVMYUCLGCJIGRM-UHFFFAOYSA-N 5-[(6-bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN(C=C(Br)C=C2)C2=N1 RVMYUCLGCJIGRM-UHFFFAOYSA-N 0.000 claims description 3
- RVDFNMVVTJLOKM-UHFFFAOYSA-N 5-[(8-bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CN(C=CC=C2Br)C2=N1 RVDFNMVVTJLOKM-UHFFFAOYSA-N 0.000 claims description 3
- WWBILVRRJWOXOT-UHFFFAOYSA-N 5-[[2-(1,3-dimethylpyrazol-4-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CN(C)N=C1C WWBILVRRJWOXOT-UHFFFAOYSA-N 0.000 claims description 3
- QWEQPUNEMMXLLA-UHFFFAOYSA-N 5-[[2-(2,4-dimethylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=C(C)C=NN1C QWEQPUNEMMXLLA-UHFFFAOYSA-N 0.000 claims description 3
- ZRZFYNFUTOCKJN-UHFFFAOYSA-N 5-[[2-(2,5-dimethylpyrazol-3-yl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC(C)=NN1C ZRZFYNFUTOCKJN-UHFFFAOYSA-N 0.000 claims description 3
- VSNROGDZROBWJU-UHFFFAOYSA-N 6-methyl-3-(pyridin-3-ylmethoxy)pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CN=C1 VSNROGDZROBWJU-UHFFFAOYSA-N 0.000 claims description 3
- PISBHLQNUDLFRW-UHFFFAOYSA-N 6-methyl-3-(quinolin-2-ylmethoxy)pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=C(C=CC=C2)C2=N1 PISBHLQNUDLFRW-UHFFFAOYSA-N 0.000 claims description 3
- ZTVHGGATAWRQLW-UHFFFAOYSA-N 6-methyl-3-(quinolin-3-ylmethoxy)pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CN=C(C=CC=C2)C2=C1 ZTVHGGATAWRQLW-UHFFFAOYSA-N 0.000 claims description 3
- MWTKSMGJWLBAPF-UHFFFAOYSA-N 6-methyl-3-[(1-methylpyrazolo[3,4-b]pyridin-5-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CN=C(N(C)N=C2)C2=C1 MWTKSMGJWLBAPF-UHFFFAOYSA-N 0.000 claims description 3
- QTRMHTUFUFJGSM-UHFFFAOYSA-N 6-methyl-3-[(2-pyrazol-1-ylpyridin-3-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CN=C1N1N=CC=C1 QTRMHTUFUFJGSM-UHFFFAOYSA-N 0.000 claims description 3
- OUSNUPGOACPDDX-UHFFFAOYSA-N 8-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]imidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC(C#N)=CN2C1=NC=C2 OUSNUPGOACPDDX-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010011985 Decubitus ulcer Diseases 0.000 claims description 3
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 3
- 208000025865 Ulcer Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000008445 altitude sickness Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- RNUKDHQSFPHXFX-UHFFFAOYSA-N methyl 2-bromo-8-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]imidazo[1,2-a]pyridine-6-carboxylate Chemical compound C12=NC(Br)=CN2C=C(C(=O)OC)C=C1COC1=CN=C(OC)C=C1C=O RNUKDHQSFPHXFX-UHFFFAOYSA-N 0.000 claims description 3
- JCTHZEDSZIFTFR-UHFFFAOYSA-N methyl 8-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]imidazo[1,2-a]pyridine-6-carboxylate Chemical compound C12=NC=CN2C=C(C(=O)OC)C=C1COC1=CN=C(OC)C=C1C=O JCTHZEDSZIFTFR-UHFFFAOYSA-N 0.000 claims description 3
- 208000023504 respiratory system disease Diseases 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 231100000397 ulcer Toxicity 0.000 claims description 3
- DXLPQBMKYQAGIC-UHFFFAOYSA-N 2-(2-imidazo[1,2-a]pyridin-8-ylethyl)pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1CCC1=CC=CN2C1=NC=C2 DXLPQBMKYQAGIC-UHFFFAOYSA-N 0.000 claims description 2
- ZBKPRNJPWHJIAX-UHFFFAOYSA-N 2-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1OCC1=CN(C=CC=C2)C2=N1 ZBKPRNJPWHJIAX-UHFFFAOYSA-N 0.000 claims description 2
- LKRKFDAARRUYHF-UHFFFAOYSA-N 2-methoxy-5-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C2C=NC=CN2N=C1 LKRKFDAARRUYHF-UHFFFAOYSA-N 0.000 claims description 2
- AYDRVKKVDYOYBH-UHFFFAOYSA-N 2-methoxy-5-[[2-(1h-pyrazol-5-yl)quinolin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC2=CC=CC=C2N=C1C1=CC=NN1 AYDRVKKVDYOYBH-UHFFFAOYSA-N 0.000 claims description 2
- RGZTUOZMJYGNNV-UHFFFAOYSA-N 3-(1h-indazol-4-ylmethoxy)-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC2=C1C=NN2 RGZTUOZMJYGNNV-UHFFFAOYSA-N 0.000 claims description 2
- QLZVWQMILQSOAP-UHFFFAOYSA-N 3-(1h-pyrrolo[2,3-b]pyridin-4-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=CC=NC2=C1C=CN2 QLZVWQMILQSOAP-UHFFFAOYSA-N 0.000 claims description 2
- XYDYPEHDNDNXBL-UHFFFAOYSA-N 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)pyridine-2-carbaldehyde Chemical compound O=CC1=NC=CC=C1OCC1=CC=CN2C1=NC=C2 XYDYPEHDNDNXBL-UHFFFAOYSA-N 0.000 claims description 2
- BWOUTBABNRAAAC-UHFFFAOYSA-N 3-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=C2C=NC=CN2N=C1 BWOUTBABNRAAAC-UHFFFAOYSA-N 0.000 claims description 2
- GMDNYTOZMJZQQU-UHFFFAOYSA-N 3-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1OCC1=CC=C2N1C=CN=C2 GMDNYTOZMJZQQU-UHFFFAOYSA-N 0.000 claims description 2
- DKGHXCOIHYUSOR-UHFFFAOYSA-N 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methylpyridine-4-carbaldehyde Chemical compound C1=NC(C)=CC(C=O)=C1OCC1=CC=CN2C1=NC=C2 DKGHXCOIHYUSOR-UHFFFAOYSA-N 0.000 claims description 2
- XBDXQLJIWXNBDQ-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyridine-3-carboxylic acid Chemical compound N1=CC(C(=O)O)=CC=C1COC1=CN=CC=C1C=O XBDXQLJIWXNBDQ-UHFFFAOYSA-N 0.000 claims description 2
- ZOEYRYLTSCMZOA-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyrrolo[1,2-a]pyrazine-7-carbonitrile Chemical compound O=CC1=CC=NC=C1OCC1=C(C#N)C=C2N1C=CN=C2 ZOEYRYLTSCMZOA-UHFFFAOYSA-N 0.000 claims description 2
- OIYRUDQLJOPQNT-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyrrolo[1,2-a]pyrazine-7-carboxamide Chemical compound NC(=O)C=1C=C2C=NC=CN2C=1COC1=CN=CC=C1C=O OIYRUDQLJOPQNT-UHFFFAOYSA-N 0.000 claims description 2
- GHENCMPQPXFARP-UHFFFAOYSA-N 6-methoxy-3-[(1-methylindazol-6-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(OC)=CC=C1OCC1=CC=C(C=NN2C)C2=C1 GHENCMPQPXFARP-UHFFFAOYSA-N 0.000 claims description 2
- JCLICOHGBJZLIW-UHFFFAOYSA-N 8-[(3-formylpyridin-2-yl)oxymethyl]imidazo[1,2-a]pyridine-6-carboxamide Chemical compound C12=NC=CN2C=C(C(=O)N)C=C1COC1=NC=CC=C1C=O JCLICOHGBJZLIW-UHFFFAOYSA-N 0.000 claims description 2
- PTMRXCFRFLKQBX-UHFFFAOYSA-N methyl 4-[(2-formylpyridin-3-yl)oxymethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1COC1=CC=CN=C1C=O PTMRXCFRFLKQBX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 16
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 274
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 231
- 239000000203 mixture Substances 0.000 description 226
- 238000005160 1H NMR spectroscopy Methods 0.000 description 135
- 235000019439 ethyl acetate Nutrition 0.000 description 128
- 239000000243 solution Substances 0.000 description 116
- 239000007787 solid Substances 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 100
- 238000002360 preparation method Methods 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 66
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 64
- 239000000741 silica gel Substances 0.000 description 63
- 229910002027 silica gel Inorganic materials 0.000 description 63
- 239000003480 eluent Substances 0.000 description 61
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
- 239000012044 organic layer Substances 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000007832 Na2SO4 Substances 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 39
- 229910052938 sodium sulfate Inorganic materials 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- 229910000027 potassium carbonate Inorganic materials 0.000 description 33
- 229910002092 carbon dioxide Inorganic materials 0.000 description 30
- 108010016797 Sickle Hemoglobin Proteins 0.000 description 29
- 239000010410 layer Substances 0.000 description 29
- 125000005843 halogen group Chemical group 0.000 description 28
- 125000000217 alkyl group Chemical group 0.000 description 27
- 239000001301 oxygen Substances 0.000 description 26
- 108010054147 Hemoglobins Proteins 0.000 description 25
- 102000001554 Hemoglobins Human genes 0.000 description 25
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 25
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 238000000746 purification Methods 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- 239000000546 pharmaceutical excipient Substances 0.000 description 17
- GRJJLRLFOQLVKR-UHFFFAOYSA-N 5-hydroxy-2-methoxypyridine-4-carbaldehyde Chemical compound COC1=CC(C=O)=C(O)C=N1 GRJJLRLFOQLVKR-UHFFFAOYSA-N 0.000 description 15
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 230000003281 allosteric effect Effects 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 229910006124 SOCl2 Inorganic materials 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 238000003556 assay Methods 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- JWDZEPQEQCIVJH-UHFFFAOYSA-N 2-methoxy-5-(methoxymethoxy)pyridine Chemical compound COCOC1=CC=C(OC)N=C1 JWDZEPQEQCIVJH-UHFFFAOYSA-N 0.000 description 5
- CLADBSZPHROUKB-UHFFFAOYSA-N 2-methoxy-5-(methoxymethoxy)pyridine-4-carbaldehyde Chemical compound COCOC1=CN=C(OC)C=C1C=O CLADBSZPHROUKB-UHFFFAOYSA-N 0.000 description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QIQZUABMLGJKJP-UHFFFAOYSA-N (2-bromopyridin-3-yl)methanol Chemical compound OCC1=CC=CN=C1Br QIQZUABMLGJKJP-UHFFFAOYSA-N 0.000 description 4
- GEMCNTAYIYTBJF-ZRDIBKRKSA-N (e)-1-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-2-yl]-3-(dimethylamino)prop-2-en-1-one Chemical compound CN(C)\C=C\C(=O)C1=NC=CC=C1CO[Si](C)(C)C(C)(C)C GEMCNTAYIYTBJF-ZRDIBKRKSA-N 0.000 description 4
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- UKTHRMMETXCGBZ-UHFFFAOYSA-N 3-(chloromethyl)-2-(2-propan-2-ylpyrazol-3-yl)pyridine;hydrochloride Chemical compound Cl.CC(C)N1N=CC=C1C1=NC=CC=C1CCl UKTHRMMETXCGBZ-UHFFFAOYSA-N 0.000 description 4
- ZOPFFHDCXLZOSS-UHFFFAOYSA-N 3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridine-2-carbonitrile Chemical compound C=1C=CN=C(C#N)C=1COC=1C=NC(OC)=CC=1C1OCCO1 ZOPFFHDCXLZOSS-UHFFFAOYSA-N 0.000 description 4
- VPYYBRWSCLINST-UHFFFAOYSA-N 5-hydroxy-2-(2-methoxyethoxy)pyridine-4-carbaldehyde Chemical compound COCCOC1=CC(C=O)=C(O)C=N1 VPYYBRWSCLINST-UHFFFAOYSA-N 0.000 description 4
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 4
- MZTRGFBICLTYAT-UHFFFAOYSA-N 6-[[4-(dimethoxymethyl)pyridin-3-yl]oxymethyl]pyridine-3-carbonitrile Chemical compound COC(OC)C1=CC=NC=C1OCC1=CC=C(C#N)C=N1 MZTRGFBICLTYAT-UHFFFAOYSA-N 0.000 description 4
- VMLCUJXSXBSUFH-UHFFFAOYSA-N 6-[[4-(dimethoxymethyl)pyridin-3-yl]oxymethyl]pyridine-3-carboxylic acid Chemical compound COC(OC)C1=CC=NC=C1OCC1=CC=C(C(O)=O)C=N1 VMLCUJXSXBSUFH-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000004438 haloalkoxy group Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- CPGMWEHTXCUZOT-UHFFFAOYSA-N 1-[3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridin-2-yl]propan-1-one Chemical compound CCC(=O)C1=NC=CC=C1COC1=CN=C(OC)C=C1C1OCCO1 CPGMWEHTXCUZOT-UHFFFAOYSA-N 0.000 description 3
- OWRYEOOYOHXZJX-UHFFFAOYSA-N 2-bromo-3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1Br OWRYEOOYOHXZJX-UHFFFAOYSA-N 0.000 description 3
- CEIDFPRFWSJEGN-UHFFFAOYSA-N 2-methoxy-5-[[2-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1COCC[Si](C)(C)C CEIDFPRFWSJEGN-UHFFFAOYSA-N 0.000 description 3
- LPFKVVZTNDJALE-UHFFFAOYSA-N 3,5-dimethoxypyridine Chemical compound COC1=CN=CC(OC)=C1 LPFKVVZTNDJALE-UHFFFAOYSA-N 0.000 description 3
- GIXOINAQOWRHSR-UHFFFAOYSA-N 3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridine-2-carboxylic acid Chemical compound C=1C=CN=C(C(O)=O)C=1COC=1C=NC(OC)=CC=1C1OCCO1 GIXOINAQOWRHSR-UHFFFAOYSA-N 0.000 description 3
- BQBUQXHOFAAIMY-UHFFFAOYSA-N 4-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridine-3,5-diol Chemical compound CC(C)(C)[Si](C)(C)OCC1=C(O)C=NC=C1O BQBUQXHOFAAIMY-UHFFFAOYSA-N 0.000 description 3
- QZANZECZJMGHBS-UHFFFAOYSA-N 5-hydroxy-2-(2-methoxyethoxy)pyridine-3-carbaldehyde Chemical compound COCCOC1=NC=C(O)C=C1C=O QZANZECZJMGHBS-UHFFFAOYSA-N 0.000 description 3
- LKBKDKVMHWPZDB-UHFFFAOYSA-N 6-methoxypyridin-3-ol Chemical compound COC1=CC=C(O)C=N1 LKBKDKVMHWPZDB-UHFFFAOYSA-N 0.000 description 3
- MIZVHVKHBWQUOG-UHFFFAOYSA-N 6-methyl-3-[(1-methylindazol-5-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=C(N(C)N=C2)C2=C1 MIZVHVKHBWQUOG-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 0 CC1*C*C1 Chemical compound CC1*C*C1 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- XUXPQBAYQZSOGY-UHFFFAOYSA-N [3,5-bis(phenylmethoxy)pyridin-4-yl]methoxy-tert-butyl-dimethylsilane Chemical compound C1=NC=C(OCC=2C=CC=CC=2)C(CO[Si](C)(C)C(C)(C)C)=C1OCC1=CC=CC=C1 XUXPQBAYQZSOGY-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 238000006392 deoxygenation reaction Methods 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000000262 haloalkenyl group Chemical group 0.000 description 3
- 125000000232 haloalkynyl group Chemical group 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- GQYRONXNOBBQGZ-UHFFFAOYSA-N methyl 3-[3-[3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-1-yl]propanoate Chemical compound COC(=O)CCN1C=CC(C=2C(=CC=CN=2)COC=2C(=CC(OC)=NC=2)C=O)=N1 GQYRONXNOBBQGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- UYZJZYVCRVEGDE-UHFFFAOYSA-N (2-bromopyridin-3-yl)methoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC=CN=C1Br UYZJZYVCRVEGDE-UHFFFAOYSA-N 0.000 description 2
- LQBUZBOVEZBDEB-UHFFFAOYSA-N (3-bromopyridin-4-yl)methanol Chemical compound OCC1=CC=NC=C1Br LQBUZBOVEZBDEB-UHFFFAOYSA-N 0.000 description 2
- FHNIWSJPXPJTRN-UHFFFAOYSA-N (3-chloroisoquinolin-4-yl)methanol Chemical compound C1=CC=C2C(CO)=C(Cl)N=CC2=C1 FHNIWSJPXPJTRN-UHFFFAOYSA-N 0.000 description 2
- NYTVRJQDIXLFAT-UHFFFAOYSA-N (3-chloropyrazin-2-yl)methanol Chemical compound OCC1=NC=CN=C1Cl NYTVRJQDIXLFAT-UHFFFAOYSA-N 0.000 description 2
- GYYXXPVOVNLYHU-WYMLVPIESA-N (e)-3-(dimethylamino)-1-[3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridin-2-yl]-2-methylprop-2-en-1-one Chemical compound C=1C=CN=C(C(=O)C(\C)=C\N(C)C)C=1COC=1C=NC(OC)=CC=1C1OCCO1 GYYXXPVOVNLYHU-WYMLVPIESA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 2
- GCBMZXMAXAVNSF-UHFFFAOYSA-N 1-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-2-yl]ethanone Chemical compound CC(=O)C1=NC=CC=C1CO[Si](C)(C)C(C)(C)C GCBMZXMAXAVNSF-UHFFFAOYSA-N 0.000 description 2
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 2
- ZKZJXVGTTZXHGX-UHFFFAOYSA-N 1-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CC(C)N1N=CC=C1B1OC(C)(C)C(C)(C)O1 ZKZJXVGTTZXHGX-UHFFFAOYSA-N 0.000 description 2
- XOHUEYCVLUUEJJ-UHFFFAOYSA-I 2,3-Diphosphoglycerate Chemical compound [O-]P(=O)([O-])OC(C(=O)[O-])COP([O-])([O-])=O XOHUEYCVLUUEJJ-UHFFFAOYSA-I 0.000 description 2
- XEHBFIRKVXTKKV-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine Chemical compound COCCOC1=CC=C(OCOC)C=N1 XEHBFIRKVXTKKV-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- CHFVPVZPIIXPBP-UHFFFAOYSA-N 2-[3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridin-2-yl]propan-2-ol Chemical compound C=1C=CN=C(C(C)(C)O)C=1COC=1C=NC(OC)=CC=1C1OCCO1 CHFVPVZPIIXPBP-UHFFFAOYSA-N 0.000 description 2
- GFNTYEKHUYDKBT-UHFFFAOYSA-N 2-methoxy-5-[[2-[4-methyl-2-(oxan-2-yl)pyrazol-3-yl]pyridin-3-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=C(C)C=NN1C1OCCCC1 GFNTYEKHUYDKBT-UHFFFAOYSA-N 0.000 description 2
- KMKWHQDNHXBOID-UHFFFAOYSA-N 2-methoxy-5-[[3-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]isoquinolin-4-yl]methoxy]pyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C(C=2N(N=CC=2)COCC[Si](C)(C)C)N=CC2=CC=CC=C12 KMKWHQDNHXBOID-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- VXBTURVUBUAFPL-UHFFFAOYSA-N 3,5-bis(phenylmethoxy)pyridine-4-carbonitrile Chemical compound C1=NC=C(OCC=2C=CC=CC=2)C(C#N)=C1OCC1=CC=CC=C1 VXBTURVUBUAFPL-UHFFFAOYSA-N 0.000 description 2
- VDXTZMRBKNIZKJ-UHFFFAOYSA-N 3,5-bis(phenylmethoxy)pyridine-4-carboxamide Chemical compound C1=NC=C(OCC=2C=CC=CC=2)C(C(=O)N)=C1OCC1=CC=CC=C1 VDXTZMRBKNIZKJ-UHFFFAOYSA-N 0.000 description 2
- WRXAZPPGFLETFR-UHFFFAOYSA-N 3,5-difluoropyridine Chemical compound FC1=CN=CC(F)=C1 WRXAZPPGFLETFR-UHFFFAOYSA-N 0.000 description 2
- WJPFKYRAVTUOIZ-UHFFFAOYSA-N 3,5-dimethoxypyridine-4-carbaldehyde Chemical compound COC1=CN=CC(OC)=C1C=O WJPFKYRAVTUOIZ-UHFFFAOYSA-N 0.000 description 2
- QXJNFHMODNVOER-UHFFFAOYSA-N 3-(chloromethyl)-2-(2-methylpyrazol-3-yl)pyridine;hydrochloride Chemical compound Cl.CN1N=CC=C1C1=NC=CC=C1CCl QXJNFHMODNVOER-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- SQCOAFGVBSQDFZ-UHFFFAOYSA-N 3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridine-2-carbohydrazide Chemical compound C=1C=CN=C(C(=O)NN)C=1COC=1C=NC(OC)=CC=1C1OCCO1 SQCOAFGVBSQDFZ-UHFFFAOYSA-N 0.000 description 2
- GVVRAUQIPLTEHK-UHFFFAOYSA-N 3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridine-2-carbonitrile Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC=CN=C1C#N GVVRAUQIPLTEHK-UHFFFAOYSA-N 0.000 description 2
- HMSMGFVSFVMHFQ-UHFFFAOYSA-N 3-chloroisoquinoline-4-carbaldehyde Chemical compound C1=CC=CC2=C(C=O)C(Cl)=NC=C21 HMSMGFVSFVMHFQ-UHFFFAOYSA-N 0.000 description 2
- XZGYPJCLQDTRAS-UHFFFAOYSA-N 3-hydroxy-5-methoxypyridine-4-carbaldehyde Chemical compound COC1=CN=CC(O)=C1C=O XZGYPJCLQDTRAS-UHFFFAOYSA-N 0.000 description 2
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 2
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 2
- OSLUFZHXRVQDJQ-UHFFFAOYSA-N 4-(1,3-dioxolan-2-yl)-2-methoxy-5-[[2-(2-propan-2-yl-1,2,4-triazol-3-yl)pyridin-3-yl]methoxy]pyridine Chemical compound C=1C=CN=C(C=2N(N=CN=2)C(C)C)C=1COC=1C=NC(OC)=CC=1C1OCCO1 OSLUFZHXRVQDJQ-UHFFFAOYSA-N 0.000 description 2
- FDWMDZKPDWDQFO-UHFFFAOYSA-N 4-(1,3-dioxolan-2-yl)-2-methoxy-5-[[2-(4-methyl-2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine Chemical compound C=1C=CN=C(C=2N(N=CC=2C)C(C)C)C=1COC=1C=NC(OC)=CC=1C1OCCO1 FDWMDZKPDWDQFO-UHFFFAOYSA-N 0.000 description 2
- AJYFSADVBFCVFT-UHFFFAOYSA-N 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol Chemical compound C1=NC(OC)=CC(C2OCCO2)=C1O AJYFSADVBFCVFT-UHFFFAOYSA-N 0.000 description 2
- KLTMKKNNTSMNHQ-UHFFFAOYSA-N 4-(dimethoxymethyl)pyridin-3-ol Chemical compound COC(OC)C1=CC=NC=C1O KLTMKKNNTSMNHQ-UHFFFAOYSA-N 0.000 description 2
- KIWHTOAPCVVXEQ-UHFFFAOYSA-N 4-(hydroxymethyl)-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridin-3-ol Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CN=CC(O)=C1CO KIWHTOAPCVVXEQ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- MDMKGAHIENKPLC-UHFFFAOYSA-N 5-(methoxymethoxy)-1h-pyridin-2-one Chemical compound COCOC1=CC=C(O)N=C1 MDMKGAHIENKPLC-UHFFFAOYSA-N 0.000 description 2
- GVXOLOOMUXOIDK-UHFFFAOYSA-N 5-(methoxymethoxy)-2-phenylmethoxypyridine Chemical compound N1=CC(OCOC)=CC=C1OCC1=CC=CC=C1 GVXOLOOMUXOIDK-UHFFFAOYSA-N 0.000 description 2
- SCIZZBFELFRYDW-UHFFFAOYSA-N 5-[(2-bromopyridin-3-yl)methoxy]-4-(1,3-dioxolan-2-yl)-2-methoxypyridine Chemical compound C=1C=CN=C(Br)C=1COC=1C=NC(OC)=CC=1C1OCCO1 SCIZZBFELFRYDW-UHFFFAOYSA-N 0.000 description 2
- SMEMHDWCEBRNBE-UHFFFAOYSA-N 5-[(3-chloroisoquinolin-4-yl)methoxy]-2-methoxypyridine-4-carbaldehyde Chemical compound C1=NC(OC)=CC(C=O)=C1OCC1=C(Cl)N=CC2=CC=CC=C12 SMEMHDWCEBRNBE-UHFFFAOYSA-N 0.000 description 2
- QWCGOMIAXFNYIV-UHFFFAOYSA-N 6-(bromomethyl)pyridine-3-carbonitrile Chemical compound BrCC1=CC=C(C#N)C=N1 QWCGOMIAXFNYIV-UHFFFAOYSA-N 0.000 description 2
- MGYPGQVMPGRVIC-UHFFFAOYSA-N 6-[[4-(dimethoxymethyl)pyridin-3-yl]oxymethyl]-n-methylsulfonylpyridine-3-carboxamide Chemical compound COC(OC)C1=CC=NC=C1OCC1=CC=C(C(=O)NS(C)(=O)=O)C=N1 MGYPGQVMPGRVIC-UHFFFAOYSA-N 0.000 description 2
- DUOZFKGYLWPYEY-UHFFFAOYSA-N 6-[[4-(dimethoxymethyl)pyridin-3-yl]oxymethyl]pyridine-2-carboxylic acid Chemical compound COC(OC)C1=CC=NC=C1OCC1=CC=CC(C(O)=O)=N1 DUOZFKGYLWPYEY-UHFFFAOYSA-N 0.000 description 2
- HLJQGGQHPBNZRE-UHFFFAOYSA-N 6-methyl-3-[(1-methylindazol-4-yl)methoxy]pyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=CC2=C1C=NN2C HLJQGGQHPBNZRE-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 229920002799 BoPET Polymers 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 108010085682 Hemoglobin A Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000005041 Mylar™ Substances 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 208000002903 Thalassemia Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- MFHUEEJBGOEVPZ-UHFFFAOYSA-N [2-(2-methylpyrazol-3-yl)pyridin-3-yl]methanol Chemical compound CN1N=CC=C1C1=NC=CC=C1CO MFHUEEJBGOEVPZ-UHFFFAOYSA-N 0.000 description 2
- UEDFWLZMMDKEDO-UHFFFAOYSA-N [2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid Chemical compound C[Si](C)(C)CCOCN1N=CC=C1B(O)O UEDFWLZMMDKEDO-UHFFFAOYSA-N 0.000 description 2
- ZWIWOEYNZMLIMG-UHFFFAOYSA-N [3,5-bis(phenylmethoxy)pyridin-4-yl]methanol Chemical compound C1=NC=C(OCC=2C=CC=CC=2)C(CO)=C1OCC1=CC=CC=C1 ZWIWOEYNZMLIMG-UHFFFAOYSA-N 0.000 description 2
- NLZKZCKNIASZGQ-UHFFFAOYSA-N [3-(2-propan-2-ylpyrazol-3-yl)pyridin-4-yl]methanol Chemical compound CC(C)N1N=CC=C1C1=CN=CC=C1CO NLZKZCKNIASZGQ-UHFFFAOYSA-N 0.000 description 2
- QGBCULWUSAFELB-UHFFFAOYSA-N [6-(1-methylpyrazol-3-yl)pyridin-3-yl]methanol Chemical compound CN1C=CC(C=2N=CC(CO)=CC=2)=N1 QGBCULWUSAFELB-UHFFFAOYSA-N 0.000 description 2
- MYRWMZACSRRKFN-UHFFFAOYSA-N [6-(1-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methanol Chemical compound CC(C)N1C=CC(C=2N=CC(CO)=CC=2)=N1 MYRWMZACSRRKFN-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229940053991 aldehydes and derivative Drugs 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 230000008848 allosteric regulation Effects 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- SNQQJEJPJMXYTR-UHFFFAOYSA-N dimethyl pyridine-2,6-dicarboxylate Chemical compound COC(=O)C1=CC=CC(C(=O)OC)=N1 SNQQJEJPJMXYTR-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- HPFQJBOXPBNOJK-UHFFFAOYSA-N ethyl 1-oxidopyridin-1-ium-3-carboxylate Chemical compound CCOC(=O)C1=CC=C[N+]([O-])=C1 HPFQJBOXPBNOJK-UHFFFAOYSA-N 0.000 description 2
- FUCIAZKOKQBGQL-UHFFFAOYSA-N ethyl 2-(aminomethyl)pyridine-3-carboxylate;hydrochloride Chemical compound [Cl-].CCOC(=O)C1=CC=CN=C1C[NH3+] FUCIAZKOKQBGQL-UHFFFAOYSA-N 0.000 description 2
- LDQNPTYEZUBCCE-UHFFFAOYSA-N ethyl 2-[5-[3-(chloromethyl)pyridin-2-yl]pyrazol-1-yl]acetate;hydrochloride Chemical compound Cl.CCOC(=O)CN1N=CC=C1C1=NC=CC=C1CCl LDQNPTYEZUBCCE-UHFFFAOYSA-N 0.000 description 2
- GSSPADQNESJYTG-UHFFFAOYSA-N ethyl 2-[5-[3-(hydroxymethyl)pyridin-2-yl]pyrazol-1-yl]acetate Chemical compound CCOC(=O)CN1N=CC=C1C1=NC=CC=C1CO GSSPADQNESJYTG-UHFFFAOYSA-N 0.000 description 2
- NWGOMTGPKPSKGI-UHFFFAOYSA-N ethyl 2-[5-[3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridin-2-yl]pyrazol-1-yl]acetate Chemical compound CCOC(=O)CN1N=CC=C1C1=NC=CC=C1COC1=CN=C(OC)C=C1C=O NWGOMTGPKPSKGI-UHFFFAOYSA-N 0.000 description 2
- KOAWFXMHARNHJY-UHFFFAOYSA-N ethyl 2-cyanopyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=CN=C1C#N KOAWFXMHARNHJY-UHFFFAOYSA-N 0.000 description 2
- IZZCPMXJHNYFKD-UHFFFAOYSA-N ethyl imidazo[1,5-a]pyridine-8-carboxylate Chemical compound CCOC(=O)C1=CC=CN2C=NC=C12 IZZCPMXJHNYFKD-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 150000002373 hemiacetals Chemical class 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- ILULYDJFTJKQAP-UHFFFAOYSA-N hydron;propan-2-ylhydrazine;chloride Chemical compound [Cl-].CC(C)N[NH3+] ILULYDJFTJKQAP-UHFFFAOYSA-N 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical group O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- ZPMLFIQEXXHNKV-UHFFFAOYSA-N imidazo[1,5-a]pyridin-8-ylmethanol Chemical compound OCC1=CC=CN2C=NC=C12 ZPMLFIQEXXHNKV-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000006194 liquid suspension Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- QZRUEPDGSBRTCP-UHFFFAOYSA-N methyl 3-[(4-formyl-6-methoxypyridin-3-yl)oxymethyl]pyridine-2-carboxylate Chemical compound COC(=O)C1=NC=CC=C1COC1=CN=C(OC)C=C1C=O QZRUEPDGSBRTCP-UHFFFAOYSA-N 0.000 description 2
- AOVOGRNPYCBERW-UHFFFAOYSA-N methyl 3-[3-[3-(chloromethyl)pyridin-2-yl]pyrazol-1-yl]propanoate;hydrochloride Chemical compound Cl.COC(=O)CCN1C=CC(C=2C(=CC=CN=2)CCl)=N1 AOVOGRNPYCBERW-UHFFFAOYSA-N 0.000 description 2
- KYQZMTSBDCKSPL-UHFFFAOYSA-N methyl 3-[3-[3-(hydroxymethyl)pyridin-2-yl]pyrazol-1-yl]propanoate Chemical compound COC(=O)CCN1C=CC(C=2C(=CC=CN=2)CO)=N1 KYQZMTSBDCKSPL-UHFFFAOYSA-N 0.000 description 2
- PLDZQDNVQYLOKA-UHFFFAOYSA-N methyl 3-[3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-2-yl]pyrazol-1-yl]propanoate Chemical compound COC(=O)CCN1C=CC(C=2C(=CC=CN=2)CO[Si](C)(C)C(C)(C)C)=N1 PLDZQDNVQYLOKA-UHFFFAOYSA-N 0.000 description 2
- DVIUNMLAPDJWHL-UHFFFAOYSA-N methyl 6-(hydroxymethyl)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(CO)=N1 DVIUNMLAPDJWHL-UHFFFAOYSA-N 0.000 description 2
- HFCLQROPOONHGU-UHFFFAOYSA-N methyl 6-[[4-(dimethoxymethyl)pyridin-3-yl]oxymethyl]pyridine-2-carboxylate Chemical compound COC(OC)C1=CC=NC=C1OCC1=CC=CC(C(=O)OC)=N1 HFCLQROPOONHGU-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- YDAUUVIUNKOMNQ-UHFFFAOYSA-N tert-butyl-dimethyl-[[2-(1h-pyrazol-5-yl)pyridin-3-yl]methoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC=CN=C1C1=CC=NN1 YDAUUVIUNKOMNQ-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000013389 whole blood assay Methods 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- LYPYZKKPXUWCKT-UHFFFAOYSA-N (1-methylindazol-4-yl)methanol Chemical compound C1=CC=C2N(C)N=CC2=C1CO LYPYZKKPXUWCKT-UHFFFAOYSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- BPZAIOKOQDGVMQ-UHFFFAOYSA-N 1-(1,3-thiazolidin-3-yl)ethanone Chemical compound CC(=O)N1CCSC1 BPZAIOKOQDGVMQ-UHFFFAOYSA-N 0.000 description 1
- BYXBTASYGXRTJA-UHFFFAOYSA-N 1-[3-[[4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yl]oxymethyl]pyridin-2-yl]ethanone Chemical compound C=1C=CN=C(C(C)=O)C=1COC=1C=NC(OC)=CC=1C1OCCO1 BYXBTASYGXRTJA-UHFFFAOYSA-N 0.000 description 1
- KDKGWGUUUVROTO-UHFFFAOYSA-N 1-hydroxypiperazine Chemical compound ON1CCNCC1 KDKGWGUUUVROTO-UHFFFAOYSA-N 0.000 description 1
- SONWSIAHVBTXPB-UHFFFAOYSA-N 1-methylindazole-4-carbaldehyde Chemical compound C1=CC=C2N(C)N=CC2=C1C=O SONWSIAHVBTXPB-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical group C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- XOHUEYCVLUUEJJ-UHFFFAOYSA-N 2,3-Bisphosphoglyceric acid Chemical compound OP(=O)(O)OC(C(=O)O)COP(O)(O)=O XOHUEYCVLUUEJJ-UHFFFAOYSA-N 0.000 description 1
- XOHUEYCVLUUEJJ-UWTATZPHSA-N 2,3-bisphospho-D-glyceric acid Chemical compound OP(=O)(O)O[C@@H](C(=O)O)COP(O)(O)=O XOHUEYCVLUUEJJ-UWTATZPHSA-N 0.000 description 1
- MGZGPQCRWVOGFE-UHFFFAOYSA-N 2,4-dihydro-1h-isoquinolin-3-one Chemical compound C1=CC=C2CNC(=O)CC2=C1 MGZGPQCRWVOGFE-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- BNKNLXGWYCWORL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine-3-carbaldehyde Chemical compound COCCOC1=NC=C(OCOC)C=C1C=O BNKNLXGWYCWORL-UHFFFAOYSA-N 0.000 description 1
- VHGXVUHPAQXAJM-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine-4-carbaldehyde Chemical compound COCCOC1=CC(C=O)=C(OCOC)C=N1 VHGXVUHPAQXAJM-UHFFFAOYSA-N 0.000 description 1
- YWRBGOXVNMQFNL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-5-[[2-(2-methylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-3-carbaldehyde Chemical compound C1=C(C=O)C(OCCOC)=NC=C1OCC1=CC=CN=C1C1=CC=NN1C YWRBGOXVNMQFNL-UHFFFAOYSA-N 0.000 description 1
- DBQUFAHLCCBOTN-UHFFFAOYSA-N 2-(chloromethyl)-3-(2-propan-2-ylpyrazol-3-yl)pyrazine;hydrochloride Chemical compound Cl.CC(C)N1N=CC=C1C1=NC=CN=C1CCl DBQUFAHLCCBOTN-UHFFFAOYSA-N 0.000 description 1
- POTMBBPVZBNZLT-UHFFFAOYSA-N 2-(imidazo[1,5-a]pyridin-8-ylmethoxy)-5-methoxypyridine-4-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CN=C1OCC1=CC=CN2C1=CN=C2 POTMBBPVZBNZLT-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical class O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- OHLFQXUZENMEDT-UHFFFAOYSA-N 2-bromo-3-(chloromethyl)pyridine;hydrochloride Chemical compound Cl.ClCC1=CC=CN=C1Br OHLFQXUZENMEDT-UHFFFAOYSA-N 0.000 description 1
- MMWNKXIFVYQOTK-UHFFFAOYSA-N 2-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Br MMWNKXIFVYQOTK-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- DFFCUUMSPSHYJL-UHFFFAOYSA-N 2-methoxy-5-[[2-(1h-pyrazol-5-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde;dihydrochloride Chemical compound Cl.Cl.C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1 DFFCUUMSPSHYJL-UHFFFAOYSA-N 0.000 description 1
- ZASCQGVJZLYWHM-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]pyridine-4-carbaldehyde;dihydrochloride Chemical compound Cl.Cl.C1=NC(OC)=CC(C=O)=C1OCC1=CC=CN=C1C1=CC=NN1C(C)C ZASCQGVJZLYWHM-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- DNTYEVWEOFZXFE-UHFFFAOYSA-N 2-oxo-1h-pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CNC1=O DNTYEVWEOFZXFE-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YHICHRLTRYAVHP-UHFFFAOYSA-N 3,5-bis(phenylmethoxy)pyridine-4-carbaldehyde Chemical compound C1=NC=C(OCC=2C=CC=CC=2)C(C=O)=C1OCC1=CC=CC=C1 YHICHRLTRYAVHP-UHFFFAOYSA-N 0.000 description 1
- MUHBRCUFWMUBNP-UHFFFAOYSA-N 3,5-dichloropyridine-4-carbonitrile Chemical compound ClC1=CN=CC(Cl)=C1C#N MUHBRCUFWMUBNP-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- QJKJHNKYQLCCGP-UHFFFAOYSA-N 3-(chloromethyl)-2-(2-methylpyrazol-3-yl)pyridine Chemical compound CN1N=CC=C1C1=NC=CC=C1CCl QJKJHNKYQLCCGP-UHFFFAOYSA-N 0.000 description 1
- WNDRBMJGRQTNMA-UHFFFAOYSA-N 3-[(3-chloro-1-methylindazol-5-yl)methoxy]-6-methylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1OCC1=CC=C(N(C)N=C2Cl)C2=C1 WNDRBMJGRQTNMA-UHFFFAOYSA-N 0.000 description 1
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 1
- AVXWWBFBRTXBRM-UHFFFAOYSA-N 3-bromopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1Br AVXWWBFBRTXBRM-UHFFFAOYSA-N 0.000 description 1
- ICDRROJXRNPLLX-UHFFFAOYSA-N 3-chloro-4-(chloromethyl)isoquinoline Chemical compound C1=CC=C2C(CCl)=C(Cl)N=CC2=C1 ICDRROJXRNPLLX-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- PMRPVXLESNMKLG-UHFFFAOYSA-N 3-chloropyrazine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN=C1Cl PMRPVXLESNMKLG-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WYLVNASPZUFUJS-UHFFFAOYSA-N 3-phenylmethoxypyridine-2-carbaldehyde Chemical compound O=CC1=NC=CC=C1OCC1=CC=CC=C1 WYLVNASPZUFUJS-UHFFFAOYSA-N 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IAIQLRMHQSVYFM-UHFFFAOYSA-N 4-(chloromethyl)-1-methylindazole Chemical compound C1=CC=C2N(C)N=CC2=C1CCl IAIQLRMHQSVYFM-UHFFFAOYSA-N 0.000 description 1
- ZCTFWJYFAFBGCY-UHFFFAOYSA-N 4-(chloromethyl)-3-(2-propan-2-ylpyrazol-3-yl)pyridine;hydrochloride Chemical compound Cl.CC(C)N1N=CC=C1C1=CN=CC=C1CCl ZCTFWJYFAFBGCY-UHFFFAOYSA-N 0.000 description 1
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 1
- DYRMBQRXOMOMNW-UHFFFAOYSA-N 4-chloropyridine-3-carbaldehyde Chemical compound ClC1=CC=NC=C1C=O DYRMBQRXOMOMNW-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- RWNPFJBWAUQIMP-UHFFFAOYSA-N 4-phenylmethoxypyridine-3-carbaldehyde Chemical compound O=CC1=CN=CC=C1OCC1=CC=CC=C1 RWNPFJBWAUQIMP-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 description 1
- DBGGDAAQLLDHSS-UHFFFAOYSA-N 5-phenylmethoxypyridine-2-carbaldehyde Chemical compound C1=NC(C=O)=CC=C1OCC1=CC=CC=C1 DBGGDAAQLLDHSS-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- QCPYQKMLEZPHAN-UHFFFAOYSA-N 6-[(4-formylpyridin-3-yl)oxymethyl]pyridine-3-carbonitrile Chemical compound O=CC1=CC=NC=C1OCC1=CC=C(C#N)C=N1 QCPYQKMLEZPHAN-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- PBLOYQAQGYUPCM-UHFFFAOYSA-N 6-methylpyridine-3-carbonitrile Chemical compound CC1=CC=C(C#N)C=N1 PBLOYQAQGYUPCM-UHFFFAOYSA-N 0.000 description 1
- VKPWAEVWZUALPZ-UHFFFAOYSA-N 6-phenylmethoxypyridin-3-ol Chemical compound N1=CC(O)=CC=C1OCC1=CC=CC=C1 VKPWAEVWZUALPZ-UHFFFAOYSA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QKWWHWXIZVRRNK-UHFFFAOYSA-N 8-(chloromethyl)imidazo[1,2-a]pyridine Chemical compound ClCC1=CC=CN2C=CN=C12 QKWWHWXIZVRRNK-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- XLSPUCCTJJFXSW-UHFFFAOYSA-N CC(C)c1cc2ccccc2nc1 Chemical compound CC(C)c1cc2ccccc2nc1 XLSPUCCTJJFXSW-UHFFFAOYSA-N 0.000 description 1
- VFNKVFOXIVOADS-UHFFFAOYSA-N CC(c(cc1C=O)c(C)nc1OCc1ccccc1)(F)F Chemical compound CC(c(cc1C=O)c(C)nc1OCc1ccccc1)(F)F VFNKVFOXIVOADS-UHFFFAOYSA-N 0.000 description 1
- CPSINPPHRWIGCT-UHFFFAOYSA-N CC(c(cc1C=O)c(C)nc1OCc1ccccc1)O Chemical compound CC(c(cc1C=O)c(C)nc1OCc1ccccc1)O CPSINPPHRWIGCT-UHFFFAOYSA-N 0.000 description 1
- FPGRUEGJQQXFBC-UHFFFAOYSA-N CC1(C)C=NC=CN=C1 Chemical compound CC1(C)C=NC=CN=C1 FPGRUEGJQQXFBC-UHFFFAOYSA-N 0.000 description 1
- OAUYNMCBOPUJCL-UHFFFAOYSA-N CCOC(c1ccc(C#N)nc1)=O Chemical compound CCOC(c1ccc(C#N)nc1)=O OAUYNMCBOPUJCL-UHFFFAOYSA-N 0.000 description 1
- KSPHUCIDVPXQFN-UHFFFAOYSA-N CCc1cncc(C=O)c1CC(c1cc(cccc2)c2[nH]1)O Chemical compound CCc1cncc(C=O)c1CC(c1cc(cccc2)c2[nH]1)O KSPHUCIDVPXQFN-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- SKSOWNAVDISQIY-UHFFFAOYSA-N CN1N=NNC1 Chemical compound CN1N=NNC1 SKSOWNAVDISQIY-UHFFFAOYSA-N 0.000 description 1
- NRVIJTPZKQYJIX-UHFFFAOYSA-N COC(CC([n](cc1)nc1-c1c(CCl)cccn1)/[O]=C/c1cc(OC)ncc1O)=O Chemical compound COC(CC([n](cc1)nc1-c1c(CCl)cccn1)/[O]=C/c1cc(OC)ncc1O)=O NRVIJTPZKQYJIX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- SKAMBIQMMYJFIE-UHFFFAOYSA-N Cc(nc1C=O)c(C)nc1OCc1ccccc1 Chemical compound Cc(nc1C=O)c(C)nc1OCc1ccccc1 SKAMBIQMMYJFIE-UHFFFAOYSA-N 0.000 description 1
- PTBIIFXKVNSAMY-UHFFFAOYSA-N Cc(ncc(CO)c1C=O)c1OCc1ccccc1 Chemical compound Cc(ncc(CO)c1C=O)c1OCc1ccccc1 PTBIIFXKVNSAMY-UHFFFAOYSA-N 0.000 description 1
- QHRZMGDJNNDMGZ-UHFFFAOYSA-N Cc1c(ccnc2)c2ccc1 Chemical compound Cc1c(ccnc2)c2ccc1 QHRZMGDJNNDMGZ-UHFFFAOYSA-N 0.000 description 1
- KDYVCOSVYOSHOL-UHFFFAOYSA-N Cc1cc2ncccc2cc1 Chemical compound Cc1cc2ncccc2cc1 KDYVCOSVYOSHOL-UHFFFAOYSA-N 0.000 description 1
- LMYVCXSKCQSIEQ-UHFFFAOYSA-N Cc1cccc2c1cccn2 Chemical compound Cc1cccc2c1cccn2 LMYVCXSKCQSIEQ-UHFFFAOYSA-N 0.000 description 1
- ZCSOPXICDLUYPX-UHFFFAOYSA-N Cc1nc(OCc2ccccc2)c(/C=[O]/c(nccc2C=O)c2OCc2ccccc2)cc1 Chemical compound Cc1nc(OCc2ccccc2)c(/C=[O]/c(nccc2C=O)c2OCc2ccccc2)cc1 ZCSOPXICDLUYPX-UHFFFAOYSA-N 0.000 description 1
- VAGQOYGWIXSICP-UHFFFAOYSA-N Cc1ncc(CO)c(C=O)c1OCc(cccc1)c1C(O)=O Chemical compound Cc1ncc(CO)c(C=O)c1OCc(cccc1)c1C(O)=O VAGQOYGWIXSICP-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000034502 Haemoglobin C disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001032845 Homo sapiens Metabotropic glutamate receptor 5 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Chemical group OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 150000008538 L-cysteines Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 102000036675 Myoglobin Human genes 0.000 description 1
- 108010062374 Myoglobin Proteins 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 1
- 102000013009 Pyruvate Kinase Human genes 0.000 description 1
- 108020005115 Pyruvate Kinase Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- FXKDDCBFUOGTQM-UHFFFAOYSA-N [2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methanol Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1CO FXKDDCBFUOGTQM-UHFFFAOYSA-N 0.000 description 1
- HSQNSGXSDRTELF-UHFFFAOYSA-N [3-(2-propan-2-ylpyrazol-3-yl)pyrazin-2-yl]methanol Chemical compound CC(C)N1N=CC=C1C1=NC=CN=C1CO HSQNSGXSDRTELF-UHFFFAOYSA-N 0.000 description 1
- VWHLNQRRCVKGAR-UHFFFAOYSA-N [4-methyl-2-(oxan-2-yl)pyrazol-3-yl]boronic acid Chemical compound OB(O)C1=C(C)C=NN1C1OCCCC1 VWHLNQRRCVKGAR-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-L benzylidene(dichloro)ruthenium;tricyclohexylphosphane Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-L 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- CWHBCTLVWOCMPQ-UHFFFAOYSA-L disodium;2-[(3,5-diiodo-4-oxidophenyl)-(3,5-diiodo-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]benzoate Chemical group [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C(C=1C=C(I)C([O-])=C(I)C=1)=C1C=C(I)C(=O)C(I)=C1 CWHBCTLVWOCMPQ-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HZZRIIPYFPIKHR-UHFFFAOYSA-N ethyl 2-hydrazinylacetate;hydron;chloride Chemical compound Cl.CCOC(=O)CNN HZZRIIPYFPIKHR-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- REYZKMUTDRFIFK-UHFFFAOYSA-N formic acid;5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1h-pyridine-4-carbaldehyde Chemical compound OC=O.O=CC1=CC(=O)NC=C1OCC1=CC=CN2C1=NC=C2 REYZKMUTDRFIFK-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 229940125926 hemoglobin modulator Drugs 0.000 description 1
- 208000034737 hemoglobinopathy Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-YPZZEJLDSA-N iodine-125 Chemical compound [125I] ZCYVEMRRCGMTRW-YPZZEJLDSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 description 1
- QKLFOLOIKNGNCL-UHFFFAOYSA-N isoquinoline;pyridine Chemical class C1=CC=NC=C1.C1=NC=CC2=CC=CC=C21 QKLFOLOIKNGNCL-UHFFFAOYSA-N 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000005980 lung dysfunction Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 1
- PQIILISJLIOFHU-UHFFFAOYSA-N methyl 4-[(3-formyl-2h-pyridin-3-yl)oxymethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1COC1(C=O)C=CC=NC1 PQIILISJLIOFHU-UHFFFAOYSA-N 0.000 description 1
- YTQKJVLJTRNZLE-UHFFFAOYSA-N methyl 5-(chloromethyl)pyridine-3-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1=CN=CC(CCl)=C1 YTQKJVLJTRNZLE-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- IHCHOVVAJBADAH-UHFFFAOYSA-N n-[2-hydroxy-4-(1h-pyrazol-4-yl)phenyl]-6-methoxy-3,4-dihydro-2h-chromene-3-carboxamide Chemical compound C1C2=CC(OC)=CC=C2OCC1C(=O)NC(C(=C1)O)=CC=C1C=1C=NNC=1 IHCHOVVAJBADAH-UHFFFAOYSA-N 0.000 description 1
- LPOIGVZLNWEGJG-UHFFFAOYSA-N n-benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 LPOIGVZLNWEGJG-UHFFFAOYSA-N 0.000 description 1
- 239000002055 nanoplate Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000005254 oxyacyl group Chemical group 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical class O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000000637 radiosensitizating effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- DCQXTYAFFMSNNH-UHFFFAOYSA-M sodium;2-[bis(2-hydroxyethyl)amino]ethanol;acetate Chemical compound [Na+].CC([O-])=O.OCCN(CCO)CCO DCQXTYAFFMSNNH-UHFFFAOYSA-M 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- FXUAIOOAOAVCGD-WCTZXXKLSA-N swainsonine Chemical compound C1CC[C@@H](O)[C@@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-WCTZXXKLSA-N 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- OXNFGOJSHSSDKE-UHFFFAOYSA-N tert-butyl-dimethyl-[[2-(1-methylpyrazol-3-yl)pyridin-3-yl]methoxy]silane Chemical compound CN1C=CC(C=2C(=CC=CN=2)CO[Si](C)(C)C(C)(C)C)=N1 OXNFGOJSHSSDKE-UHFFFAOYSA-N 0.000 description 1
- NHTAJSQFZHOJMK-UHFFFAOYSA-N tert-butyl-dimethyl-[[2-(2-methylpyrazol-3-yl)pyridin-3-yl]methoxy]silane Chemical compound CN1N=CC=C1C1=NC=CC=C1CO[Si](C)(C)C(C)(C)C NHTAJSQFZHOJMK-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- HHLJUSLZGFYWKW-UHFFFAOYSA-N triethanolamine hydrochloride Chemical class Cl.OCCN(CCO)CCO HHLJUSLZGFYWKW-UHFFFAOYSA-N 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention generally relates to substituted heteroaryl aldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and said substituted heteroaryl aldehydes and derivatives thereof for use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation.
- Hemoglobin is a tetrameric protein in red blood cells that transports up to four oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes, and is in the tense (T) state when it is unbound to oxygen and in the relaxed (R) state when it is bound to oxygen. The equilibrium between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its de-oxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states have also been found, however their role in allosteric regulation has not been fully elucidated.
- Sickle cell disease is a prevalent disease particularly among those of African and Mediterranean descent.
- Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing the T state to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape.
- the sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels.
- Certain synthetic aldehydes have been found to shift the equilibrium from the polymer forming T state to the non-polymer forming R state ( Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769 ) by acting as allosteric modulators to stabilize the R state through formation of a Schiff base with an amino group on hemoglobin.
- US 7,160,910 discloses 2-furfuraldehydes and related compounds that are also allosteric modulators of hemoglobin.
- One particular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found to be a potent hemoglobin modulator both in vitro and in vivo.
- Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, the 5HMF treated mice were also found to have reduced amounts of hypoxia-induced sickled red blood cells as compared to the non-treated mice.
- Such therapeutics would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiotherapy or chemotherapy due to the low levels of oxygen in the cell, to treating pulmonary and hypertensive disorders, and to promoting wound healing.
- WO 00/75145 describes compounds useful for treating inflammation, pharmaceutical compositions comprising said compounds and methods of inhibiting/treating inflammatory diseases in a mammal.
- Manna et al. (Il Farmaco, 1996, 51(8,9), 579-587 ) describes the synthesis of [ ⁇ 3-(alkylamine)-2-hydroxypropyl ⁇ -2-oximino]pyridines and O -[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes, and their ⁇ -adrenoreceptor blocking activity in vitro and in vivo.
- Pubchem compound CID 54009805 is 4-phenylmethoxypyridine-3-carbaldehyde.
- US 4,410,537 describes ether compounds which are said to have medicinal value in the palliation of haemoglobinopathies and pulmonary dysfunction, protection from the effects of hypoxia and the radiosensitization of tumours.
- WO 99/48490 describes compounds which allosterically modify pyruvate kinase and either inhibit or activate enzymatic activity.
- US 2003/0022923 describes the preparation and use of a protected organic aldehyde wherein bioavailability of the orally administered therapeutic aldehyde is improved.
- the present invention provides a compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, for use in a method for treating a condition associated with oxygen deficiency wherein:
- the present invention also provides a compound of Formula (I'), or a tautomer or pharmaceutically acceptable salt thereof wherein:
- the present invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Forumla (I') as defined above, or a tautomer or pharmaceutically acceptable salt thereof.
- Alkoxy refers to -O(alkyl) where alkyl is as defined herein.
- Representative examples of alkoxy groups include methoxy, ethoxy, t -butoxy, and the like.
- Alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated.
- C 1-8 alkyl refers to a hydrocarbon radical straight or branched, containing from 1 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
- Alkyl includes branched chain isomers of straight chain alkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like.
- Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
- Alkenyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but no more than three double bonds.
- C 2-8 alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.
- Alkynyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix.
- alkynyl is also meant to include those alkyl groups having one triple bond and one double bond.
- C 2-8 alkynyl is meant to include ethynyl, propynyl and the like.
- allosteric modulators refers to compounds that bind to hemoglobin to modulate its affinity for oxygen.
- the allosteric modulators act to stabilize or destabilize a particular hemoglobin conformation.
- the modulators stabilize the relaxed R state.
- the modulators destabilize the tense T state.
- the allosteric modulators can destabilize one conformation while stabilizing another.
- the modulators stabilize a relaxed R state and destabilize the tense T state.
- the modulators in addition to modulating the affinity of hemoglobin for oxygen, may also confer additional properties to hemoglobin such as increasing its solubility.
- the present disclosure is not intended to be limited to the mechanism by which the allosteric modulators interact with and regulate hemoglobin.
- the allosteric modulators inhibit the polymerization of HbS and the sickling of red blood cells.
- the binding of the allosteric modulators provided herein to hemoglobin can occur through covalent or non-covalent interactions.
- the allosteric modulators react through its aldehyde substituent with an amine group on a hemoglobin amino acid side chain to form a Schiff base.
- Amino refers to a monovalent radical -NH 2 .
- Aryl by itself or as part of another substituent refers to a polyunsaturated, aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
- the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example.
- aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.
- Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
- C u'-v' cycloalkyl refers to cycloalkyl groups having u' to v' carbon atoms as ring members.
- C u'-v' cycloalkenyl refers to cycloalkenyl groups having u' to v' carbon atoms as ring members.
- hemoglobin refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle hemoglobin (HbS).
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms.
- Heteroaryl groups include polycyclic aromatic ring(s) fused to non-aromatic cycloalkyl or heterocycloalkyl groups, and where the point of attachment to the remainder of the molecule can be through any suitable ring atom of any ring.
- the ring heteroatom(s) can be in either an aromatic or non-aromatic ring or both.
- aromatic ring include any ring having at least one planar resonance structure where 2n+2 pi electrons are delocalized about the ring.
- heteroaryl groups include, but are not limited to, imidazopyridinyl groups, pyrrolopyridinyl groups, pyrazolopyridinyl groups, triazolopyridinyl groups, pyrazolopyrazinyl groups, pyridinyl groups, pyrazinyl groups, oxazolyl groups, imidazolyl groups, triazolyl groups, tetrazolyl groups, pyrazolyl groups, quinolinyl groups, isoquinolinyl groups, indazolyl groups, benzooxazolyl groups, naphthyridinyl groups, and quinoxalinyl groups.
- heteroaryl groups include xanthine, hypoxanthine, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, azaindole, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
- heterocycloalkyl refers to a cycloalkyl group containing at least one ring heteroatom and optionally one or more oxo substituents.
- heteroatom is meant to include oxygen (O), nitrogen (N), and sulfur (S), wherein the heteroatoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- Each heterocycle can be attached at any available ring carbon or heteroatom.
- Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together.
- Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms.
- these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms.
- heterocycle groups include morpholin-3-one, piperazine-2-one, piperazin-1-oxide, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrrolidine, and the like.
- Halo or halogen by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+1), where m' is the total number of carbon atoms in the alkyl group.
- haloC 1-8 alkyl is meant to include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- haloalkenyl and “haloalkynyl” refers to alkenyl and alkynyl radicals having one or more halogen atoms.
- haloalkoxy refers to an alkoxy radical substituted with one or more halogen atoms.
- the haloakyl, haloalkenyl, haloalkynyl, and haloalkoxy groups have from one to 5 or from one to 3 halo atoms.
- haloalkoxy groups include difluoromethoxy and trifluoromethoxy.
- the halo atoms of the haloalkenyl and haloalkynyl groups are attached to the aliphatic portions of these groups.
- heteroaryl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heteroaryl group is substituted with an alkyl group and situations where the heteroaryl group is not substituted with the alkyl group.
- C 1-8 designating a number of atoms e.g. "C 1-8 " is meant to include all possible embodiments that have one fewer atom.
- Non-limiting examples include C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 2-8 , C 2-7 , C 3-8 , C 3-7 and the like.
- salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
- Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p -tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19, 1977 ).
- Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- pharmaceutically acceptable carrier or excipient means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
- a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
- pharmaceutically effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
- Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY .
- Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
- hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
- aldehyde protecting group refers to any known protecting group used to mask the aldehyde functionality.
- Aldehyde protecting groups include acetals and hemiacetals.
- the acetals and hemiacetals can be prepared from C 1-8 alcohols or C 2-8 diols.
- the aldehyde protecting group may be a five or six membered cyclic acetal formed from condensation of the aldehyde with ethylene or propylene glycol.
- the aldehyde protecting group may be an imine or hydroxyimine.
- the aldehyde protecting group may be a thiazolidine or N-acetylthiazolidine prodrug group
- the aldehyde protecting group may be a thiazolidine prodrug group disclosed in US 6,355,661 .
- the modulators provided herein may be condensed with L-cysteine or a L-cysteine derivative to form the corresponding thiazolidine protected aldehyde prodrug.
- Said thiazolidine may have the formula wherein R 11 is selected from the group consisting of OH, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, N(R 13 ) 2 where R 13 is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 12 is H or -L-R 14 , where L is carbonyl or sulfonyl; R 14 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; the wavy line signifies the point of attachment to the phenyl ring of the allosteric modulators disclosed herein; and the term "substituted" refers to substitution by one or more substituents
- Sickle cell disease refers to diseases mediated by sickle hemoglobin (HbS) that results from a single point mutation in the hemoglobin (Hb).
- Sickle cell diseases includes sickle cell anemia, sickle-hemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/ ⁇ + ) and sickle beta-zero-thalassaemia (HbS/ ⁇ 0 ).
- the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
- a person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.
- treat includes partially or completely delaying, alleviating, mitigating or reducing the intensity, progression, or worsening of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition.
- Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
- wavy line signifies the point of attachment of the substituent to the remainder of the molecule.
- the point of attachment can be to any suitable atom of the substituent.
- the wavy line in the following structure is intended to include, as the point of attachment, any of the six substitutable carbon atoms.
- Stereomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. "Stereoisomer” and “stereoisomers” refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers.
- stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
- enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
- An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory ( i.e., as (+) or (-)-isomers respectively).
- a chiral compound can exist as either individual enantiomer or as a mixture thereof.
- a mixture containing equal proportions of the enantiomers is called a "racemic mixture".
- the description is intended to include individual stereoisomers as well as mixtures.
- the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art ( see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992 ) differ in the chirality of one or more stereocenters.
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with isotopes, such as for example deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
- impermissible substitution patterns are well known to the skilled artisan.
- z in the Formula (I) is 1. In another group of embodiments, z is 2. In still another group of embodiments, z is 3.
- the compound of Formula (I) is not
- a compound having Formula (Il): or a tautomer or pharmaceutically acceptable salt thereof is provided.
- a compound having Formula (Im): or a tautomer or pharmaceutically acceptable salt thereof is provided.
- At least one R a is heteroaryl optionally substituted with one to three R c .
- At least one R a is heteroaryl attached to Q at the ring atom adjacent to ring atom bearing Y.
- At least one R a is heteroaryl substituted with at least one C 1-8 alkyl. In one group of embodiments, at least one R a heteroaryl is substituted with at least one methyl.
- At least one R a is pyrazolyl substituted with at least one C 1-8 alkyl. In one group of embodiments, at least one R a is pyrazoyl substituted with at least one C 1-8 alkyl. In one group of embodiments, at least one R a is pyrazol-5-yl. In one group of embodiments, at least one R a is 4-methyl-pyrazol-5-yl.
- Q is a heteroaryl or heterocycloalkyl group optionally substituted with one to three R a .
- Q is a bicyclic heteroaryl or heterocycloalkyl group optionally substituted with one to three R a .
- Q is a bicyclic heteroaryl group optionally substituted with one to three R a .
- Q is a bicyclic heteroaryl group substituted with one to three R a .
- Q is isoquinolin-4-yl optionally substituted with one to three R a wherein at least one R a is heteroaryl optionally substituted with one to three R c .
- at least one R a is heteroaryl attached to said Q at the ring atom adjacent to ring atom bearing Y.
- at least one R a is heteroaryl substituted with at least one C 1-8 alkyl.
- at least one R a heteroaryl is substituted with at least one methyl.
- At least one R a is pyrazolyl substituted with at least one C 1-8 alkyl. In one group of embodiments at least one R a is pyrazoyl substituted with at least one methyl. In one group of embodiments, R a is pyrazol-5-yl. In one group of embodiments, R a is 4-methyl-pyrazol-5-yl.
- Q is selected from the group consisting of and naphthalene containing two to four ring nitrogen atoms, each optionally substituted with one to three R a and wherein the wavy line signifies the point of attachment to Y.
- Q is selected from the group consisting of wherein Q is optionally substituted with one to three R a .
- Q is selected from the group consisting of
- Q is substituted with CONR d R d , NR d R d , or heteroaryl optionally substituted with one to three R c . In one group of embodiments, Q is substituted with heteroaryl having one to two nitrogen ring atoms.
- Q is not unsubstituted pyridin-2-yl, unsubstituted pyridin-3-yl, or unsubstituted pyridine-4-yl. In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, each of which is substituted with one to three R c .
- Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with CN or CONR d R d .
- Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with one to three R a wherein at least one R a is heteroaryl optionally substituted with one to three R c .
- at least one R a is heteroaryl attached to said Q at the ring atom adjacent to ring atom bearing Y.
- at least one R a is heteroaryl substituted with at least one C 1-8 alkyl.
- at least one R a heteroaryl is substituted with at least one methyl.
- At least one R a is pyrazolyl substituted with at least one C 1-8 alkyl. In one group of embodiments at least one R a is pyrazoyl substituted with at least one methyl. In one group of embodiments, R a is pyrazol-5-yl. In one group of embodiments, R a is 4-methyl-pyrazol-5-yl.
- Q is substituted with at least one R a selected from the group consisting of -(CH 2 ) k OH, -(CH 2 ) k NH 2 , -(CH 2 ) k NH(C 1-8 alkyl), -(CH 2 ) k N(C 1-8 alkyl)(C 1-8 alkyl), -(CH 2 ) k NHC(O)(C 1-8 alkyl), -(CH 2 ) k N(C 1-8 alkyl)C(O)(C 1-8 alkyl), -(CH 2 ) k NHC(O) 2 (C 1-8 alkyl), -(CH 2 ) k N(C 1-8 alkyl)C(O) 2 (C 1-8 alkyl), -(CH 2 ) k NHS(O) 2 (C 1-8 alkyl), -(CH 2 ) k N(C 1-8 alkyl)S(O) 2 (C 1-8 alkyl),
- heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C(O)C 1-8 alkyl, -C(O) 2 C 1-8 alkyl, or -S(O) 2 C 1-8 alkyl.
- Q is substituted with at least one R a selected from the group consisting of -NR d (CH 2 ) k OH, -NR d (CH 2 ) k NH 2 , -NR d (CH 2 ) k NH(C 1-8 alkyl), -NR d (CH 2 ) k N(C 1-8 alkyl)(C 1-8 alkyl), -NR d (CH 2 ) k NHC(O)(C 1-8 alkyl), -NR d (CH 2 ) k N(C 1-8 alkyl)C(O)(C 1-8 alkyl), -NR d (CH 2 ) k NHC(O) 2 (C 1-8 alkyl), -NR d (CH 2 ) k NHC(O) 2 (C 1-8 alkyl), -NR d (CH 2 ) k N(C 1-8 alkyl)C(O) 2 (C 1-8 alkyl), -NR d (CH 2
- R d is H or C 1-8 alkyl.
- the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C(O)C 1-8 alkyl, -C(O) 2 C 1-8 alkyl, or -S(O) 2 C 1-8 alkyl.
- Q is substituted with at least one R a selected from the group consisting of O(CH 2 ) k OH, O(CH 2 ) k NH 2 , O(CH 2 ) k NH(C 1-8 alkyl), O(CH 2 ) k N(C 1-8 alkyl)(C 1-8 alkyl), O(CH 2 ) k NHC(O)(C 1-8 alkyl), O(CH 2 ) k N(C 1-8 alkyl)C(O)(C 1-8 alkyl), O(CH 2 ) k NHC(O) 2 (C 1-8 alkyl), O(CH 2 ) k N(C 1-8 alkyl)C(O) 2 (C 1-8 alkyl), O(CH 2 ) k NHS(O) 2 (C 1-8 alkyl), O(CH 2 ) k N(C 1-8 alkyl)S(O) 2 (C 1-8 alkyl), and O(CH 2 ) k hetero
- heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C(O)C 1-8 alkyl, -C(O) 2 C 1-8 alkyl, or -S(O) 2 C 1-8 alkyl.
- T 1 is C and R 2 is H.
- T 2 is C and R 3 is H.
- T 4 is C and R 5 is H.
- T 3 is C and R 4 is C 1-8 alkoxy.
- R 2 , R 3 , R 5 when present are H and R 4 is C 1-8 alkoxy.
- R 4 is methoxy
- R 4 is haloalkoxy. In one group of embodiments, R 4 is OCHF 2 . In one group of embodiments, R 4 is OCF 3 .
- R 2 , R 3 , R 4 , and R 5 when present are H.
- one of R 2 , R 3 , R 4 , and R 5 is selected from the group consisting of -O(CH 2 ) z OH, -O(CH 2 ) z NH 2 , -O(CH 2 ) z NH(C 1-8 alkyl), and -O(CH 2 ) z N(C 1-8 alkyl)(C 1-8 alkyl) where z is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.
- X is O.
- X is CH 2 .
- the compound of Formula (I) is not:
- the invention provides compounds of Formula (Ib): or a tautomer or pharmaceutically acceptable salt thereof, for use as defined above, wherein:
- the invention provides compounds for use of Formula Ib wherein R 2 and R 3 are independently absent or selected from the group consisting of hydrogen, R b , OR d , O(CH 2 ) z OR d , O(CH 2 ) z NR d R d , OC(O)R e , CO 2 R d , CONR d R d , and C(O)R d , where z is 1, 2, or 3.
- the invention provides compounds for use of Formula Ib wherein at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. No z is 0.
- the invention provides compounds for use of Formula Ib wherein T 2 is N; T 1 , T 3 , and T 4 are C; R 2 and R 5 are H; R 3 is absent; and R 4 is C 1-8 alkoxy.
- the invention provides compounds for use of Formula Ib wherein T 2 is N; T 1 , T 3 , and T 4 are C; R 2 and R 5 are H; R 3 is absent; and R 5 is selected from hydroxy and C 1-8 alkoxy.
- the invention provides compounds for use of Formula Ib wherein T 4 is N; T 1 , T 2 , and T 3 are C; R 2 and R 3 are H; R 5 is absent; and R 4 is selected from C 1-8 alkyl and C 1-8 alkoxy.
- the invention provides compounds for use of Formula Ib wherein T 1 is N; T 2 , T 3 , and T 4 are C; R 3 , R 4 , and R 5 are H; and R 2 is absent.
- the invention provides compounds for use of Formula Ib wherein T 2 is N; T 1 , T 3 , and T 4 are C; R 2 , R 4 , and R 5 are H; and R 3 is absent.
- the invention provides compounds for use of Formula Ib wherein T 3 is N; T 1 , T 2 , and T 4 are C; R 2 , R 3 , and R 5 are H; and R 4 is absent.
- the invention provides compounds for use of Formula Ib wherein T 4 is N; T 1 , T 2 , and T 3 are C; R 2 , R 3 , and R 4 are H; and R 5 is absent.
- the invention provides compounds for use of Formula Ib wherein Q is selected from an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three R a .
- the invention provides compounds of Formula (I'), wherein R 2 and R 3 are independently absent or selected from the group consisting of hydrogen, R b , OR d , O(CH 2 ) z OR d , O(CH 2 ) z NR d R d , OC(O)R e , CO 2 R d , CONR d R d , and C(O)R d , where z is 1, 2, or 3.
- the invention provides compounds of Formula (I'), wherein T 2 is N; R 2 and R 5 are H; R 3 is absent; and R 4 is C 1-8 alkoxy, haloC 1-8 alkoxy, and O(CH 2 ) 2 C 1-8 alkyl.
- the invention provides compounds of Formula (I'), wherein T 2 is N; R 2 and R 4 are H; R 3 is absent; and R 5 is selected from hydroxy and C 1-8 alkoxy.
- the invention provides compounds of Formula (I'), wherein T 4 is N; R 2 and R 3 are H; R 5 is absent; and R 4 is selected from C 1-8 alkyl and C 1-8 alkoxy.
- the invention provides compounds of Formula (I'), or another group of embodiments of Formula (I') that is disclosed herein, wherein Q is selected from the group consisting of an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three R a .
- the invention provides compounds of Formula (I'), or another group of embodiments of Formula (I') that is disclosed herein, wherein Q is selected from the group consisting of: and wherein Q is optionally substituted with one to three R a .
- the invention provides compounds of Formula (I') wherein at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. No z is 0.
- the compounds of Formula (I) and/or (I'), or tautomers or pharmaceutically acceptable salts thereof are selected from Table 1 below.
- Table 1 Table 1.
- Compound Structure Name 1 4-(pyridin-3-ylmethoxy)nicotinaldehyde 2 3-(pyridin-3-ylmethoxy)isonicotinaldehyde 3 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)nicotinaldehyde 4 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)picolinaldehyde 5 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde 6 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde 7 3-(imidazo[1,5-a]pyridin-8-ylmethoxy)isonicotinaldehyde 8 2-methoxy-5
- the compound of Formula (I) and/or Formula (I') is selected from:
- a pharmaceutical composition comprising a compound of Formula (I') or a tautomer or pharmaceutically acceptable salt thereof.
- provided is a compound in any of the Examples or Tables which is according to Formula (I'), or a compound for use as defined above in any of the Examples or Tables which is according to Formula (I).
- provided are any combinations of subembodiments as disclosed herein including any combination of elements disclosed herein including the a selection of any single elements.
- the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.
- Also disclosed herein is an intermediate compound used in the preparation of the compounds disclosed herein.
- Scheme I shows a synthetic route for the synthesis of the compounds of Formula (I) where X is O and Y is CH 2 .
- Phenol 1.1 is contacted with intermediate 1.2 in the presence of base under ether forming conditions to give ether 1.3, where Lg represents a leaving group such as a halogen leaving group.
- Lg represents a leaving group such as a halogen leaving group.
- the compounds of Formula (I) can be prepared using the appropriate starting materials where the OH moiety of intermediate 1.1 is replaced with a leaving group and the Lg group of intermediate 1.2 is replaced with an OH group.
- Scheme II shows an example of a synthetic route for the synthesis of the compounds of Formula (I) where X and Y are CH 2 .
- Alkene 2.1 is contacted with alkene 2.2 under metathesis forming conditions in the presence of an appropriate transition metal catalyst.
- Suitable catalysts include ruthenium catalysts such as Grubbs' catalyst.
- Product 2.3 is then hydrogenated to give compound 2.4.
- Scheme IV shows an example of synthesis of the compounds of Formula (I) where Q is pyridine-3-yl and R a heteroaryl.
- Acid 4.1 is reduced to alcohol 4.2 using known methods such as by forming the anhydride (e.g. treatment with triethylamine and i -butyl chloroformate) followed by reduction with NaBH 4 .
- Alcohol 4.2 is converted to chloride 4.3 such as by treatment with thionyl chloride.
- Coupling of the halide with alcohol 4.4 under ether forming conditions gives the precursor 4.5 that can be functionalized with a variety to heteroaryl R a groups.
- 4.5 can be coupled with pyrazole 4.6 under known organometallic coupling conditions (e.g. Pd(PPh 3 ) 4 ) to give 4.7, where PG is a nitrogen protecting group such as a silyl protecting group that can be removed to give the product 4.8.
- organometallic coupling conditions e.g. Pd(PPh 3
- the protecting group can be removed using methods known to those skilled in the art.
- the compounds of the present invention may generally be utilized as the free base.
- the compounds of this invention may be used in the form of acid addition salts.
- any of the above embodiments may also be combined with other embodiments listed herein, to form other embodiments of the invention.
- listing of groups includes embodiments wherein one or more of the elements of those groups is not included.
- the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, preferably in unit dosage form suitable for single administration of a precise dosage.
- the compositions may contain suitable pharmaceutically-acceptable excipients, including adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
- suitable pharmaceutically-acceptable excipients include adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
- “Pharmaceutically acceptable excipient” refers to an excipient or mixture of excipients which does not interfere with the effectiveness of the biological activity of the active compound(s) and which is not toxic or otherwise undesirable to the subject to which it is administered.
- conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
- Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in water or an aqueous excipient, such as, for example, water, saline, aqueous dextrose, and the like, to form a solution or suspension.
- the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary excipients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
- auxiliary excipients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
- the composition will generally take the form of a tablet or capsule, or it may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used excipients such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending excipients. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional excipients for incorporation into an oral formulation include preservatives, suspending agents, thickening agents, and the like.
- Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions or liposomal formulations.
- the sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
- compositions of this invention may also be formulated in lyophilized form for parenteral administration.
- Lyophilized formulations may be reconstituted by addition of water or other aqueous medium and then further diluted with a suitable diluent prior to use.
- the liquid formulation is generally a buffered, isotonic, aqueous solution.
- suitable diluents are isotonic saline solution, 5% dextrose in water, and buffered sodium or ammonium acetate solution.
- Pharmaceutically acceptable solid or liquid excipients may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating use of the pharmaceutical composition in the treatment of of the indicated disease.
- the pharmaceutical composition may additionally contain one or more other pharmacologically active agents in addition to a compound of this invention.
- a therapeutically effective dose may vary depending upon the route of administration and dosage form.
- the representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index.
- the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
- the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
- the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, and the time of administration, rate of excretion, drug combination, judgment of the treating physician and severity of the particular disease being treated.
- the amount of active ingredient(s) will also depend upon the particular compound and other therapeutic agent, if present, in the composition.
- the compounds of the present invention may be useful for increasing tissue oxygenation, when a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof is administered to a subject in need thereof.
- a compound for use in a method for treating a condition associated with oxygen deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof, and further wherein the condition is selected from the group consisting of sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound.
- a compound for use in a method for treating a condition associated with oxygen deficiency as defined above comprising administering to a subject in need thereof a therapeutically effective amount of a compound Formula (I) as defined herein.
- the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22 ; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals ; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65 .
- the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
- the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20°C to about 75°C.
- Examples 6-13 were synthesized according to Example 5.
- Examples 26-35 were synthesized according to the procedure in Example 25.
- Examples 37- 45 were prepared according to Example 36.
- Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 mL) at -78 °C.
- the reaction mixture was warm to rt, quenched with aqueous citric acid solution, and extracted with EtOAc (50 mL) twice.
- TMSCN trimethylsilyl cyanide
- Examples 57-62 were prepared according to the procedure in Example 55.
- Example 60 Preparation of 5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (Compound 175).
- the pH of the aqueous layer was adjust to pH 6-7, filtered, and purified by RP-HPLC (Gemini 21.2 x 150 mm) with a mixture of CH 3 CN and water (0.1% HCOOH) as eluent to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde formate (82.5 mg, 31%) as an yellow solid.
- Methylmagnesium bromide (3M/ether, 2.0 mL, 5.65 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (1180 mg, 3.76 mmol, 1 eq.) in THF (10.0 mL) at -78 °C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (30 mL) twice.
- Methylmagnesium bromide (3M/ether, 0.25 mL, 0.75 mmol, 3.0 eq.) was added to a stirred solution of 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (82 mg, 0.25 mmol, 1 eq.) in THF (5.0 mL) at -78 °C. After addition, the reaction mixture was warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (20 mL) twice.
- Example 76 Preparation of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde and 5-hydroxy-2 - (2-methoxyethoxy)nicotinaldehyde.
- the mixture was then stirred at -40 °C for 1 h, quenched with a mixture of HCl (12 N, 12 mL) and THF (28 mL), warmed to rt, and added water (20 mL). The pH of the mixture was adjusted to pH 8-9 with solid K 2 CO 3 . The aqueous layer was extracted with EtOAc (30 mL) twice.
- Ethylmagnesium bromide (3M/ether, 1.53 mL, 4.60 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (960 mg, 3.07 mmol, 1 eq.) in THF (15.0 mL) at -78 °C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (2 x 30 mL).
- the crude product (100 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column,5um,19 ⁇ 150mm,; mobile phase, water with 0.05%TFA and MeCN (10% MeCN up to 35% in 4 min, up to 100% in 1 min,down to 10% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 49 mg (38%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-2-carboxylic acid as a light yellow solid.
- 2#-AnalyseHPLC-SHIMADZU(HPLC-10) Column, SunFire Prep C18 OBD Column,5um,19 ⁇ 150mm,; mobile phase, water with 0.05%TFA and MeCN (10% MeCN up to 35% in 4 min, up to 100% in 1 min,down
- Examples 88 and 89 were prepared according to example 87 above.
- Example 88 Preparation of methyl 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (Compound 200).
- the crude product (50 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um,19 ⁇ 150mm,; mobile phase, Water and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min,down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 8 mg (10%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carbonitrile as a white solid.
- LC-MS-PH-GBT-ZL-HS-13-0 (ES, m/z):258 [M+1+18] + .
- the crude product (70 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5um,19 ⁇ 150mm; mobile phase, water (0.05%HCl) and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min,down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 30 mg (31%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carboxylic acid hydrochloride as a white solid. The compound exhibited a melting point of 192-194°C.
- Example 95 Modulation of Hemoglobin Oxygen Affinity by Heteroaryl Aldehydes-Assay Procedure.
- Oxygen equilibrium curves (OEC) in purified Hemoglobin S (HbS) were measured by the change in p50, the partial pressure of oxygen at which the heme binding sites in the HbS sample are 50% saturated with oxygen.
- HbS was purified by a modified procedure (Antonini and Brunori, 1971; Heomoglobin and Myoglobin in their Reactions with Ligands; North Holland Publishing Company; Amsterdam, London) from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval.
- Oxygen equilibrium curves were carried out with a HEMOX analyzer, (TCS Scientific, New Hope, PA).
- the deoxygenation curves for both HbS alone (control) and HbS in the presence of compound were collected with the TCS software.
- the p50 for purified Hbs was typically 13.8 + 1.6.
- Delta p50 values were obtained from the p50 value for control minus the p50 value for HbS treated with compound divided by the p50 value for the control.
- a positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.
- Example 96 Modulation of Hemoglobin Oxygen Affinity by Heteroaryl Aldehydes-Assay Results.
- delta p50% Compound delta p50 1 + 2 ++ (100 ⁇ M) 3 + 4 + 5 ++ 6 + 7 + 12 + (100 ⁇ M) 38 + 39 + 40 + (100 ⁇ M) 41 + 42 + 43 ++ 44 +++ 45 +++ 46 ++ 47 + 48 ++ (100 ⁇ M) 49 ++ 52 + (100 ⁇ M) 53 ++ 54 ++ (100 ⁇ M) 55 + (100 ⁇ M) 56 + (100 ⁇ M) 57 ++ (100 ⁇ M) 58 ++ 59 + 61 + 62 + 63 +++ 64 + 65 ++ 66 ++ 70 + 71 + 74 ++ 75 + 76 + 77 + 78 + 79 ++ 80 ++ 81 + 82 + 83 + 84 ++ 85 + 86 ++ 87 + 88 + 89 + 90 + 91 ++ 92 ++ 93 ++ 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 ++ 104 + 105 + 106 ++ 107
- HbS is purified by the CRO VIRUSYS, from blood obtained from homozygous sickle cell patients through the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval.
- Compounds are prepared in 100% DMSO and a desired amount is added to 50 ⁇ M of purified HBS at a final DMSO concentration of 0.3%.
- Final potassium phosphate concentration is adjusted to 1.8 M using a combination of 2.5 M potassium phosphate stock solution and water at pH 7.4.
- the reaction mixture is incubated for an hour at 37 °C and then transferred into a 24-well plate for deoxygenation in a glove box containing 99.5 % nitrogen and 0.5% oxygen.
- the 24-well plate is not covered and incubated at 4 °C on a plate cooler inside the glove box for one and a half hours.
- Fifty ⁇ L of the reaction mixture is transferred into a 96-well plate and the absorbance at 700 nm is measured every minute for one hour at 37 °C in a plate reader located inside the glove box.
- a plot of the absorbance against time is fitted using a Boltzman sigmoidal fit and the delay time (from zero to time at half Vmax) is measured.
- delay times are expressed as percent delay (%DT), which is defined as the difference in delay times for HBS/compound and HBS alone multiplied by 100 and divided by the delay time for HBS alone.
- Activity ranges are defined by the number of dagger ( ⁇ ) symbols indicated. ⁇ denotes activity ⁇ 40% but ⁇ 80%; ⁇ ⁇ denotes activity > 80% but ⁇ 120%; ⁇ ⁇ ⁇ denotes activity > 120% but ⁇ 140%; ⁇ ⁇ ⁇ ⁇ denotes activity > 160%. Table 3.
- % delta Delay Compound % delta Delay 5 ⁇ 108 130 ⁇ 132 91 149 ⁇ 150 ⁇ 158 ⁇ 179 159 ⁇ 160 ⁇ 161 162 ⁇ 173 ⁇ 174 ⁇ 195 ⁇ 198 ⁇ 175 ⁇ 162 ⁇ 203 ⁇ 163 ⁇ 181 ⁇ 206 ⁇ 178 ⁇ 180 ⁇ 199 ⁇ 176 ⁇ 177 ⁇ 202 ⁇ 187 ⁇ 164 ⁇ 165 ⁇ 169 ⁇ 186 ⁇ 188 ⁇ 189 ⁇ 190 ⁇
- R/T assay A relaxed-to-tense transition assay (“R/T assay”) was used to determine the ability of substituted benzaldehyde compounds to mantain the high-oxygen affinity relaxed (R) state of hemoglobin under deoxygenated conditions. This ability can be expressed as a "delta R" value (i.e., the change in the time-period of the R state after hemoglobin is treated with a compound, as compared to the period without treatment with the comound). Delta R is the %R to remaining after the compounds treatment compared with no treatment (e.g. if R% without treatment is 8% while with treatment with a target compound is 48% R at 30 ⁇ M, then %R is 40% for that compound.
- delta R is the %R to remaining after the compounds treatment compared with no treatment (e.g. if R% without treatment is 8% while with treatment with a target compound is 48% R at 30 ⁇ M, then %R is 40% for that compound.
- HbS/A A mixture of HbS/A was purified from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval.
- DPG diphosphoglycerate
- Table 4 below lists the delta R values where + indicates a delta R of between 0 and 30, ++ indicates a delta R of between 30 and 50, and +++ indicates a delta R of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 30 ⁇ M. Table 4.
- Oxygen Equilibrium Curves (OEC) of whole blood before and after treatment with different concentrations of substituted benzaldehyde compounds were performed as follows using a HEMOX analyzer (TCS Scientific, New Hope, PA). Blood samples from homozygous sickle cell patients were obtained though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. The hematocrit was adjusted to 20% using autologous plasma and the blood samples were incubated for 1 hour at 37 °C in absence or presence of compounds.
- Table 5 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and +++ indicates a delta p50% of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 1000 ⁇ M. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen. Table 5.
- delta p50% Values for Whole Blood Assay Compound delta p50% 5 + 44 + 58 + 65 + 74 ++ 79 + 80 + 92 + 93 + 103 + 106 + 108 + 120 + 129 ++ 130 ++ 131 + 132 ++ 133 + 140 + 143 + 149 +++ 150 +++ 194 + 158 + 179 ++ 159 +++ 160 +++ 191 +++ 173 +++ 174 +++ 195 +++ 196 ++ 198 +++ 175 +++ 162 +++ 209 + 163 +++ 181 +++ 206 +++ 178 ++ 180 +++ 199 + 176 +++ 177 +++ 183 +++ 184 +++ 200 +++ 201 + 202 + 187 + 164 ++ 165 + 169 ++ 186 +++ 188 +++ 189 +++ 190 +++
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
- The present invention generally relates to substituted heteroaryl aldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and said substituted heteroaryl aldehydes and derivatives thereof for use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation.
- Hemoglobin (Hb) is a tetrameric protein in red blood cells that transports up to four oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes, and is in the tense (T) state when it is unbound to oxygen and in the relaxed (R) state when it is bound to oxygen. The equilibrium between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its de-oxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states have also been found, however their role in allosteric regulation has not been fully elucidated.
- Sickle cell disease is a prevalent disease particularly among those of African and Mediterranean descent. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing the T state to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. Certain synthetic aldehydes have been found to shift the equilibrium from the polymer forming T state to the non-polymer forming R state (Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) by acting as allosteric modulators to stabilize the R state through formation of a Schiff base with an amino group on hemoglobin.
-
US 7,160,910 discloses 2-furfuraldehydes and related compounds that are also allosteric modulators of hemoglobin. One particular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found to be a potent hemoglobin modulator both in vitro and in vivo. Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, the 5HMF treated mice were also found to have reduced amounts of hypoxia-induced sickled red blood cells as compared to the non-treated mice. - A need exists for therapeutics that can shift the equilibrium between the deoxygenated and oxygenated states of Hb to treat disorders that are mediated by Hb or by abnormal Hb such as HbS. A need also exists for therapeutics to treat disorders that would benefit from having Hb in the R state with an increased affinity for oxygen. Such therapeutics would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiotherapy or chemotherapy due to the low levels of oxygen in the cell, to treating pulmonary and hypertensive disorders, and to promoting wound healing.
Heimgärtner et al. (Tetrahedron, 2005, 61, 643-655) describes an efficient synthesis of (-)-swainsonine and (-)-2,8a-di-epi-swainsonine starting from readily available 2-pyridinecarbaldehyde and 3-hydroxypyridine. Lin et al. (J Med Chem, 1972, 15(6), 615-618) describes the synthesis of a series of derivatives of 3- and 5-benzyloxy-2-formylpyridine thiosemicarboazone, and their antineoplastic activity. Desideri et al. (Eur J Med Chem, 1991, 26, 455-460) describes the synthesis of some guanylhydrazones of (3-benzyloxy)-2-pyridinecarboxaldehyde and of (2-substituted 3-pyridinyloxy)acetaldehyde, and their possible activity as inhibitors of prostanoid biosynthesis in human serum. II Hong et al. (J Pharm Sci, 1970, 59(11), 1637-1645) describes the synthesis of a series of 5-substituted pyrimidine-6-carboxaldehydes and their derivatives, and their inhibitory properties of the Ehrlich ascites carcinoma and Ehrlich carcinoma. Epsztajn et al. (Tetrahedron, 1991, 47(9), 1697-1706) describes the synthesis and metallation of 4-chloropicolin- and 2-chloroisonicotinanilides. Gibson et al. (J Med Chem, 2009, 52, 4370-4379) describes the development of highly potent B2 receptor antagonists with a molecular weight of approximately 500 g/mol. Bradbury et al. (J Med Chem, 1993, 36, 1245-1254) describes a series of nonpeptide angiotensin II receptor antagonists. Wendt et al. (Bioorg Med Chem Lett, 2007, 17, 5396-5399) describes the synthesis and pharmacological activities of a series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists. Zhu et al. (Bioorg Med Chem Lett, 2006, 16, 3150-3155) describes the structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists.US 2004/0186077 describes specific pyridine and pyridine N-oxide analogues, biologically acceptable salts thereof, related compounds, related pharmaceutical compositions, and methods for treating various disorders using such compositions.WO 00/75145 US 4,410,537 describes ether compounds which are said to have medicinal value in the palliation of haemoglobinopathies and pulmonary dysfunction, protection from the effects of hypoxia and the radiosensitization of tumours.WO 99/48490 US 2003/0022923 describes the preparation and use of a protected organic aldehyde wherein bioavailability of the orally administered therapeutic aldehyde is improved. -
- Y is CH2;
- X is O or CH2;
- T1, T2, T3, and T4 are C or N, provided that at least one, but no more than one of T1, T2, T3, and T4 is N;
- Q is selected from the group consisting of
- i) heteroaryl optionally substituted with one to three Ra; wherein R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;
- ii) aryl substituted with one to three -(CH2)kCO2Rd; wherein
R2 and R5 are independently absent or selected from the group consisting of hydrogen, halo, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R3 and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; - iii) unsubstituted aryl; wherein
R2, R3, and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R5 is absent or is ORd; and - iv) heterocycloalkyl optionally substituted with one to three Ra; wherein R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;
- each Ra is independently selected from the group consisting of halo, Rb, ORd, O(CH2)uORd, O(CH2)uNRdRd, O(CH2)uNRdC(O)Re, O(CH2)uNRdC(O)2Re, O(CH2)uNRdS(O)2Re, NH2, -(CH2)kOC(O)Re, -(CH2)kSRd, CN, NO2, -(CH2)kCO2(C1-8alkyl)OH, -(CH2)kCO2(C1-8alkyl)(heteroaryl)C(O)(C1-8alkyl), -(CH2)kCO2Rd, -(CH2)kCONRdRd, -(CH2)kNRdC(O)Re, -(CH2)kNRdC(O)2Re, -(CH2)kC(O)Rd, -(CH2)kOC(O)NRdRd, -NRd(CH2)uORd, NRd(CH2)uNRdRd, -NRd(CH2)uNRdC(O)Re, -NRd(CH2)uNRdC(O)2Re, -NRd(CH2)uNRdS(O)2Re, -(CH2)kNRdC(O)2Rd, -(CH2)kNRdC(O)NRdRd, -(CH2)kS(O)Re, -(CH2)kS(O)2Re, -(CH2)kNRdS(O)2Re, -C(O)(CH2)kNRdS(O)2Re, -(CH2)kC(O)NRdS(O)2Re, -(CH2)kS(O)2NRdRd, N3, -(CH2)karyl optionally substituted with one to three Rc, -NRd(CH2)karyl optionally substituted with one to three Rc, -(CH2)kheteroaryl optionally substituted with one to three Rc, -NRd(CH2)kheteroaryl optionally substituted with one to three Rc, -(CH2)kheterocycloalkyl optionally substituted with one to three Rc, and -NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;
- each Rb is independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and C2-8alkynyl, each optionally independently substituted with one to three halo, ORd, or NRdRd;
- each Rc is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, haloC2-8alkynyl, (CH2)mORf, OC(O)Rg, SRf, CN, NO2, (CH2)mCO2Rf, CONRfRf, C(O)Rf, OC(O)NRfRf, (CH2)mNRfRf, NRfC(O)Rg, NRfC(O)2Rg, NRfC(O)NRfRf, S(O)Rg, S(O)2Rg, NRfS(O)2Rg, S(O)2NRfRf, N3, (Rf)mSiC1-8alkyl, heteroaryl optionally substituted with one to three Rh, cycloalkyl optionally substituted with one to three Rh, and heterocycloalkyl optionally substituted with one to three Rh where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;
- each Rh is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, ORj, OC(O)R, SRj, NO2, CO2Rj, CONRjRj, C(O)Rj, OC(O)NRjRj, NRjRj, NRjC(O)Rt, NRjC(O)2Rt, NRjC(O)NRjRj, S(O)Rt, S(O)2Rt, NRjS(O)2Rt, and S(O)2NRjRj;
- Rd, Rf, and Rj are each independently selected from the group consisting of hydrogen, C1-8 alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl; and
- Re, Rg, and Rt are each independently selected from the group consisting of C1-8alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl;
-
- Y is CH2;
- X is O or CH2;
- T1, T2, T3, and T4 are C or N, provided that at least one, but no more than one of T1, T2, T3, and T4 is N;
- Q is selected from the group consisting of
- i) heteroaryl optionally substituted with one to three Ra; wherein
R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; - ii) aryl substituted with one to three -(CH2)kCO2Rd; wherein
R2 and R5 are independently absent or selected from the group consisting of hydrogen, halo, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R3 and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; - iii) unsubstituted aryl; wherein
R2, R3, and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R5 is absent or is ORd; and - iv) heterocycloalkyl optionally substituted with one to three Ra; wherein
R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;
- i) heteroaryl optionally substituted with one to three Ra; wherein
- each Ra is independently selected from the group consisting of halo, Rb, ORd, O(CH2)uORd, O(CH2)uNRdRd, O(CH2)uNRdC(O)Re, O(CH2)uNRdC(O)2Re, O(CH2)uNRdS(O)2Re, NH2, -(CH2)kOC(O)Re, -(CH2)kSRd, CN, NO2, -(CH2)kCO2(C1-8alkyl)OH, -(CH2)kCO2(C1-8alkyl)(heteroaryl)C(O)(C1-8alkyl), -(CH2)kCO2Rd, -(CH2)kCONRdRd, -(CH2)kNRdC(O)Re, -(CH2)kNRdC(O)2Re, -(CH2)kC(O)Rd, -(CH2)kOC(O)NRdRd, -NRd(CH2)uORd, -NRd(CH2)uNRdRd, -NRd(CH2)uNRdC(O)Re, -NRd(CH2)uNRdC(O)2Re, -NRd(CH2)uNRdS(O)2Re, -(CH2)kNRdC(O)2Rd, -(CH2)kNRdC(O)NRdRd, -(CH2)kS(O)Re, -(CH2)kS(O)2Re, -(CH2)kNRdS(O)2Re, -C(O)(CH2)kNRdS(O)2Re, -(CH2)kC(O)NRdS(O)2Re, -(CH2)kS(O)2NRdRd, N3, -(CH2)karyl optionally substituted with one to three Rc, -NRd(CH2)karyl optionally substituted with one to three Rc, -(CH2)kheteroaryl optionally substituted with one to three Rc, -NRd(CH2)kheteroaryl optionally substituted with one to three Rc, -(CH2)kheterocycloalkyl optionally substituted with one to three Rc, and -NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;
- each Rb is independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and C2-8alkynyl, each optionally independently substituted with one to three halo, ORd, or NRdRd;
- each Rc is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, haloC2-8alkynyl, (CH2)mORf, OC(O)Rg, SRf, CN, NO2, (CH2)mCO2Rf, CONRfRf, C(O)Rf, OC(O)NRfRf, (CH2)mNRfRf, NRfC(O)Rg, NRfC(O)2Rg, NRfC(O)NRfRf, S(O)Rg, S(O)2Rg, NRfS(O)2Rg, S(O)2NRfRf, N3, (Rf)mSiC1-8alkyl, heteroaryl optionally substituted with one to three Rh, cycloalkyl optionally substituted with one to three Rh, and heterocycloalkyl optionally substituted with one to three Rh where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;
- each Rh is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, ORj, OC(O)R, SRj, NO2, CO2Rj, CONRjRj, C(O)Rj, OC(O)NRjRj, NRjRj, NRjC(O)Rt, NRjC(O)2Rt, NRjC(O)NRjRj, S(O)Rt, S(O)2Rt, NRjS(O)2Rt, and S(O)2NRjRj;
- Rd, Rf, and Rj are each independently selected from the group consisting of hydrogen, C1-8 alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl; and
- Re, Rg, and Rt are each independently selected from the group consisting of C1-8alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl,
- a) T2 is N; R2 and R5 are H; R3 is absent; and R4 is selected from C1-8alkoxy, haloC1-8alkoxy, and O(CH2)2OC1-8alkyl;
- b) T2 is N; R2 and R4 are H; R3 is absent; and R5 is selected from hydroxy and C1-8alkoxy; or
- c) T4 is N; R2 and R3 are H; R5 is absent; and R4 is selected from C1-8alkyl and C1-8alkoxy.
- The present invention further provides a pharmaceutical composition comprising a compound of Forumla (I') as defined above, or a tautomer or pharmaceutically acceptable salt thereof.
- As used herein, the below terms have the following meanings unless specified otherwise.
- The abbreviations used herein are conventional, unless otherwise defined: aq = aqueous; Boc = t-butylcarboxy, (Boc)2O = di-tert-butyl dicarbonate, °C = degrees celcius, mCPBA = m-chloroperoxybenzoic acid, DCM = dichloromethane (CH2Cl2), DIBAL = diisobutylaluminum hydride, DIEA = diisopropylethyl amine; DMF = dimethyl formamide, EtOAc = ethyl acetate, EtOH = ethanol, g = gram, H2 = hydrogen; H2O = water; HBr = hydrogen bromide; HCl = hydrogen chloride, HPLC = high pressure liquid chromatography, h = hour, LAH = lithium aluminum hydride (LiAlH4); MeCN = acetonitrile; LRMS = Low Resolution Mass Spectrum MS = Mass Spectrum, m/z = mass to charge ratio, MHz = Mega Hertz, MeOH = methanol, µM = micromolar, µL = microliter, mg = milligram, mM = millimolar, mmol = millimole, mL = milliliter, min = minute, M = molar, Na2CO3 = sodium carbonate, ng = nanogram, N = Normal, NMR = nuclear magnetic resonance, Pd/C = palladium on carbon, rp = reverse phase, sat = saturated, rt = room temperature, SEM = (2-(trimethylsilyl)ethoxy)methyl, TEA = triethylamine, THF = tetrahydrofuran, TFA = trifluoroacetic acid, TLC = thin layer chromatography, and TMS = trimethylsilyl.
- It is noted here that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.
- "Alkoxy" refers to -O(alkyl) where alkyl is as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, and the like.
- "Alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated. For example, "C1-8alkyl" refers to a hydrocarbon radical straight or branched, containing from 1 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkyl includes branched chain isomers of straight chain alkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like. Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
- "Alkenyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but no more than three double bonds. For example, C2-8alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.
- "Alkynyl" means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. The term "alkynyl" is also meant to include those alkyl groups having one triple bond and one double bond. For example, C2-8alkynyl is meant to include ethynyl, propynyl and the like.
- The term "allosteric modulators" refers to compounds that bind to hemoglobin to modulate its affinity for oxygen. In one group of embodiments, the allosteric modulators act to stabilize or destabilize a particular hemoglobin conformation. In one group of embodiments, the modulators stabilize the relaxed R state. In other embodiments, the modulators destabilize the tense T state. In one group of embodiments, the allosteric modulators can destabilize one conformation while stabilizing another. In some such embodiments, the modulators stabilize a relaxed R state and destabilize the tense T state. The modulators, in addition to modulating the affinity of hemoglobin for oxygen, may also confer additional properties to hemoglobin such as increasing its solubility. The present disclosure is not intended to be limited to the mechanism by which the allosteric modulators interact with and regulate hemoglobin. In one group of embodiments, the allosteric modulators inhibit the polymerization of HbS and the sickling of red blood cells. In one group of embodiments, the binding of the allosteric modulators provided herein to hemoglobin can occur through covalent or non-covalent interactions. In one embodiment, the allosteric modulators react through its aldehyde substituent with an amine group on a hemoglobin amino acid side chain to form a Schiff base.
- "Amino" refers to a monovalent radical -NH2.
- "Aryl" by itself or as part of another substituent refers to a polyunsaturated, aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.
- "Bond" when used as an element in a Markush group means that the corresponding group does not exist, and the groups of both sides are directly linked.
- "Cycloalkyl" refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups, a partially saturated cycloalkyl ring having at least one site of >C=C< ring unsaturation. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl. "Cu'-v'cycloalkyl" refers to cycloalkyl groups having u' to v' carbon atoms as ring members. "Cu'-v'cycloalkenyl" refers to cycloalkenyl groups having u' to v' carbon atoms as ring members.
- The term "hemoglobin" as used herein refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle hemoglobin (HbS).
- "Heteroaryl" refers to a cyclic or polycyclic radical having at least one aromatic ring and from one to five ring heteroatoms selected from N, O, and S, and optionally one or more oxo (=O) substituents attached to one or more carbon ring atoms, and wherein the nitrogen and sulfur ring atoms are optionally oxidized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms. Heteroaryl groups include polycyclic aromatic ring(s) fused to non-aromatic cycloalkyl or heterocycloalkyl groups, and where the point of attachment to the remainder of the molecule can be through any suitable ring atom of any ring. In a polycyclic heteroaryl group, the ring heteroatom(s) can be in either an aromatic or non-aromatic ring or both. The term "aromatic ring" include any ring having at least one planar resonance structure where 2n+2 pi electrons are delocalized about the ring. Examples of heteroaryl groups include, but are not limited to, imidazopyridinyl groups, pyrrolopyridinyl groups, pyrazolopyridinyl groups, triazolopyridinyl groups, pyrazolopyrazinyl groups, pyridinyl groups, pyrazinyl groups, oxazolyl groups, imidazolyl groups, triazolyl groups, tetrazolyl groups, pyrazolyl groups, quinolinyl groups, isoquinolinyl groups, indazolyl groups, benzooxazolyl groups, naphthyridinyl groups, and quinoxalinyl groups. Other non-limiting examples of heteroaryl groups include xanthine, hypoxanthine, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, azaindole, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl. "Bicyclic heteroaryl" refers to a heteroaryl radical that contains two rings.
- The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one ring heteroatom and optionally one or more oxo substituents. As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S), wherein the heteroatoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Each heterocycle can be attached at any available ring carbon or heteroatom. Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together. Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples of heterocycle groups include morpholin-3-one, piperazine-2-one, piperazin-1-oxide, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrrolidine, and the like.
- "Halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "haloC1-8alkyl" is meant to include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term "haloalkenyl", and "haloalkynyl" refers to alkenyl and alkynyl radicals having one or more halogen atoms. Additionally, term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms. In one group of embodiments, the haloakyl, haloalkenyl, haloalkynyl, and haloalkoxy groups have from one to 5 or from one to 3 halo atoms. Examples of haloalkoxy groups include difluoromethoxy and trifluoromethoxy. In one group of embodiments, the halo atoms of the haloalkenyl and haloalkynyl groups are attached to the aliphatic portions of these groups.
- The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heteroaryl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heteroaryl group is substituted with an alkyl group and situations where the heteroaryl group is not substituted with the alkyl group.
- "Oxo" refers to the divalent atom =O.
- In each of the above embodiments designating a number of atoms e.g. "C1-8" is meant to include all possible embodiments that have one fewer atom. Non-limiting examples include C1-4, C1-5, C1-6, C1-7, C2-8, C2-7, C3-8, C3-7 and the like.
- The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19, 1977). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- The term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier or excipient" as used in the specification and claims includes both one and more than one such carrier or excipient.
- The terms "pharmaceutically effective amount", "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
- "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
- The term "aldehyde protecting group" refers to any known protecting group used to mask the aldehyde functionality. Aldehyde protecting groups include acetals and hemiacetals. The acetals and hemiacetals can be prepared from C1-8 alcohols or C2-8 diols. The aldehyde protecting group may be a five or six membered cyclic acetal formed from condensation of the aldehyde with ethylene or propylene glycol. Alternatively, the aldehyde protecting group may be an imine or hydroxyimine. The aldehyde protecting group may be a thiazolidine or N-acetylthiazolidine prodrug groupThe aldehyde protecting group may be a thiazolidine prodrug group disclosed in
US 6,355,661 . The modulators provided herein may be condensed with L-cysteine or a L-cysteine derivative to form the corresponding thiazolidine protected aldehyde prodrug. Said thiazolidine may have the formula - The term "sickle cell disease" refers to diseases mediated by sickle hemoglobin (HbS) that results from a single point mutation in the hemoglobin (Hb). Sickle cell diseases includes sickle cell anemia, sickle-hemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β+) and sickle beta-zero-thalassaemia (HbS/β0).
- The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
- "Tautomer" refers to alternate forms of a molecule that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.
- The terms "treat", "treating", "treatment" and grammatical variations thereof as used herein, includes partially or completely delaying, alleviating, mitigating or reducing the intensity, progression, or worsening of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
- The symbol > when used in connection with a substituent signifies that the substituent is a divalent substituent attached to two different atoms through a single atom on the substituent.
- The term "wavy line" signifies the point of attachment of the substituent to the remainder of the molecule. When the wavy line is not depicted as being specifically appended to a specific ring atom, the point of attachment can be to any suitable atom of the substituent. For example, the wavy line in the following structure:
- Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992) differ in the chirality of one or more stereocenters.
- The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with isotopes, such as for example deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "alkoxyalkyl" refers to an alkyl group that is substituted with alkoxy and "hydroxyalkyl" refers to an alkyl group that is substituted with hydroxy. For both of these substituents, the point of attachment is at the alkyl group.
- It is understood that the definitions and formulas provided herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
- In one group of embodiments z in the Formula (I) is 1. In another group of embodiments, z is 2. In still another group of embodiments, z is 3.
-
-
- Q, Y, X, T1, T2, T3, T4, R2, R3, R4, R5, Rb, Rd, Re, Rf and Rg are as defined for Formula (I) above;
- R6 and R7 together form oxo;
- each Ra is independently selected from the group consisting of halo, Rb, ORd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdC(O)Re, NRdC(O)2Rd, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, N3, aryl optionally substituted with one to three Rc, heteroaryl optionally substituted with one to three Rc, and heterocycloalkyl optionally substituted with one to three Rc; and
each Rc is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, haloC2-8alkynyl, (CH2)mORf, OC(O)Rg, SRf, CN, NO2, CO2Rf, CONRfRf, C(O)Rf, OC(O)NRfRf, (CH2)mNRfRf, NRfC(O)Rg, NRfC(O)2Rg, NRfC(O)NRfRf, S(O)Rg, S(O)2Rg, NRfS(O)2Rg, S(O)2NRfRf, and N3 where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. -
-
-
-
-
-
- In one group of embodiments, at least one Ra is heteroaryl optionally substituted with one to three Rc.
- In one group of embodiments, at least one Ra is heteroaryl attached to Q at the ring atom adjacent to ring atom bearing Y.
- In one group of embodiments, at least one Ra is heteroaryl substituted with at least one C1-8alkyl. In one group of embodiments, at least one Ra heteroaryl is substituted with at least one methyl.
- In one group of embodiments, at least one Ra is pyrazolyl substituted with at least one C1-8alkyl. In one group of embodiments, at least one Ra is pyrazoyl substituted with at least one C1-8alkyl. In one group of embodiments, at least one Ra is pyrazol-5-yl. In one group of embodiments, at least one Ra is 4-methyl-pyrazol-5-yl.
- In one group of embodiments, Q is a heteroaryl or heterocycloalkyl group optionally substituted with one to three Ra.
- In one group of embodiments, Q is a bicyclic heteroaryl or heterocycloalkyl group optionally substituted with one to three Ra.
- In one group of embodiments, Q is a bicyclic heteroaryl group optionally substituted with one to three Ra.
- In one group of embodiments, Q is a bicyclic heteroaryl group substituted with one to three Ra. In one group of embodiments, Q is isoquinolin-4-yl optionally substituted with one to three Ra wherein at least one Ra is heteroaryl optionally substituted with one to three Rc. In one group of embodiments at least one Ra is heteroaryl attached to said Q at the ring atom adjacent to ring atom bearing Y. In one group of embodiments at least one Ra is heteroaryl substituted with at least one C1-8alkyl. In one group of embodiments at least one Ra heteroaryl is substituted with at least one methyl. In one group of embodiments at least one Ra is pyrazolyl substituted with at least one C1-8alkyl. In one group of embodiments at least one Ra is pyrazoyl substituted with at least one methyl. In one group of embodiments, Ra is pyrazol-5-yl. In one group of embodiments, Ra is 4-methyl-pyrazol-5-yl.
-
-
-
- In one group of embodiments, Q is substituted with CONRdRd, NRdRd, or heteroaryl optionally substituted with one to three Rc. In one group of embodiments, Q is substituted with heteroaryl having one to two nitrogen ring atoms.
- In one group of embodiments, Q is not unsubstituted pyridin-2-yl, unsubstituted pyridin-3-yl, or unsubstituted pyridine-4-yl. In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, each of which is substituted with one to three Rc.
- In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with CN or CONRdRd.
- In one group of embodiments, Q is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, said Q is optionally substituted with one to three Ra wherein at least one Ra is heteroaryl optionally substituted with one to three Rc. In one group of embodiments at least one Ra is heteroaryl attached to said Q at the ring atom adjacent to ring atom bearing Y. In one group of embodiments at least one Ra is heteroaryl substituted with at least one C1-8alkyl. In one group of embodiments at least one Ra heteroaryl is substituted with at least one methyl. In one group of embodiments at least one Ra is pyrazolyl substituted with at least one C1-8alkyl. In one group of embodiments at least one Ra is pyrazoyl substituted with at least one methyl. In one group of embodiments, Ra is pyrazol-5-yl. In one group of embodiments, Ra is 4-methyl-pyrazol-5-yl.
- In one group of embodiments, Q is substituted with at least one Ra selected from the group consisting of -(CH2)kOH, -(CH2)kNH2, -(CH2)kNH(C1-8alkyl), -(CH2)kN(C1-8alkyl)(C1-8alkyl), -(CH2)kNHC(O)(C1-8alkyl), -(CH2)kN(C1-8alkyl)C(O)(C1-8alkyl), -(CH2)kNHC(O)2(C1-8alkyl), -(CH2)kN(C1-8alkyl)C(O)2(C1-8alkyl), -(CH2)kNHS(O)2(C1-8alkyl), -(CH2)kN(C1-8alkyl)S(O)2(C1-8alkyl), and -(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In some embodiments the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C(O)C1-8alkyl, -C(O)2C1-8alkyl, or -S(O)2C1-8alkyl.
- In one group of embodiments, Q is substituted with at least one Ra selected from the group consisting of -NRd(CH2)kOH, -NRd(CH2)kNH2, -NRd(CH2)kNH(C1-8alkyl), -NRd(CH2)kN(C1-8alkyl)(C1-8alkyl), -NRd(CH2)kNHC(O)(C1-8alkyl), -NRd(CH2)kN(C1-8alkyl)C(O)(C1-8alkyl), -NRd(CH2)kNHC(O)2(C1-8alkyl), -NRd(CH2)kN(C1-8alkyl)C(O)2(C1-8alkyl), -NRd(CH2)kNHS(O)2(C1-8alkyl), -NRd(CH2)kN(C1-8alkyl)S(O)2(C1-8alkyl), and -NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In some embodiments, Rd is H or C1-8alkyl. In some embodiments the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C(O)C1-8alkyl, -C(O)2C1-8alkyl, or -S(O)2C1-8alkyl.
- In one group of embodiments, Q is substituted with at least one Ra selected from the group consisting of O(CH2)kOH, O(CH2)kNH2, O(CH2)kNH(C1-8alkyl), O(CH2)kN(C1-8alkyl)(C1-8alkyl), O(CH2)kNHC(O)(C1-8alkyl), O(CH2)kN(C1-8alkyl)C(O)(C1-8alkyl), O(CH2)kNHC(O)2(C1-8alkyl), O(CH2)kN(C1-8alkyl)C(O)2(C1-8alkyl), O(CH2)kNHS(O)2(C1-8alkyl), O(CH2)kN(C1-8alkyl)S(O)2(C1-8alkyl), and O(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In some embodiments the heterocycloalkyl group is morpholino or piperazinyl optionally substituted with alkyl, -C(O)C1-8alkyl, -C(O)2C1-8alkyl, or -S(O)2C1-8alkyl.
- In one group of embodiments, T1 is C and R2 is H.
- In one group of embodiments, T2 is C and R3 is H.
- In one group of embodiments, T4 is C and R5 is H.
- In one group of embodiments, T3 is C and R4 is C1-8 alkoxy.
- In one group of embodiments, R2, R3, R5 when present are H and R4 is C1-8 alkoxy.
- In one group of embodiments, R4 is methoxy.
- In one group of embodiments, R4 is haloalkoxy. In one group of embodiments, R4 is OCHF2. In one group of embodiments, R4 is OCF3.
- In one group of embodiments, R2, R3, R4, and R5 when present are H.
- In one group of embodiments, one of R2, R3, R4, and R5 is selected from the group consisting of -O(CH2)zOH, -O(CH2)zNH2, -O(CH2)zNH(C1-8alkyl), and -O(CH2)zN(C1-8alkyl)(C1-8alkyl) where z is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.
- In one group of embodiments, X is O.
- In one group of embodiments, X is CH2.
-
-
- Q, Y, X, T1, T2, T3, T4, R2, R3, R4, R5, Rb, Rc, Rd, Re, Rf, Rg, Rh, Rj and Rt are as defined above for Formula (I); and further wherein
- R2 and R3 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;
- R4 is absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, where z is 1, 2, or 3;
- R5 is absent or selected from the group consisting of hydrogen, halo, Rb, and ORd;
- R6 and R7 together form oxo;
- each Ra is independently selected from the group consisting of halo, oxo, Rb, ORd, O(CH2)uORd, O(CH2)uNRdRd, O(CH2)uNRdC(O)Re, O(CH2)uNRdC(O)2Re, O(CH2)uNRdS(O)2Re, NH2, -(CH2)kOC(O)Re, -(CH2)kSRd, CN, NO2, -(CH2)kCO2(C1-8alkyl)OH, -(CH2)kCO2(C1-8alkyl)(heteroaryl)C(O)(C1-8alkyl), -(CH2)kCO2Rd, -(CH2)kCONRdRd, -(CH2)kNRdC(O)Re, -(CH2)kNRdC(O)2Re, -(CH2)kC(O)Rd, -(CH2)kOC(O)NRdRd, -NRd(CH2)uORd, -NRd(CH2)uNRdRd, -NRd(CH2)uNRdC(O)Re, -NRd(CH2)uNRdC(O)2Re, -NRd(CH2)uNRdS(O)2Re, -(CH2)kNRdC(O)Re, -(CH2)kNRdC(O)2Rd, -(CH2)kNRdC(O)NRdRd, -(CH2)kS(O)Re, -(CH2)kS(O)2Re, -(CH2)kNRdS(O)2Re, -C(O)(CH2)kNRdS(O)2Re, -(CH2)kC(O)NRdS(O)2Re, -(CH2)kS(O)2NRdRd, N3, -(CH2)karyl optionally substituted with one to three Rc, -NRd(CH2)karyl optionally substituted with one to three Rc, -(CH2)kheteroaryl optionally substituted with one to three Rc, -NRd(CH2)kheteroaryl optionally substituted with one to three Rc, -(CH2)kheterocycloalkyl optionally substituted with one to three Rc, and -NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;
- provided that when Q is phenyl and R4 is C1-8salkyl or C2-8alkenyl, Q is substituted with at least one Ra;
- provided that when R5 is halo, Q is substituted with at least 1 Ra;
- provided that when R5 is Rb, Q is not phenyl; and
- provided that when R2, R3, R4, and R5 are H and Q is phenyl, Q is substituted with at least one Ra selected from 4-carboxy, 3-carboxy, and (C1-8 alkyl 3-carboxylate).
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein R2 and R3 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, CO2Rd, CONRdRd, and C(O)Rd, where z is 1, 2, or 3.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. No z is 0.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T2 is N; T1, T3, and T4 are C; R2 and R5 are H; R3 is absent; and R4 is C1-8alkoxy.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T2 is N; T1, T3, and T4 are C; R2 and R5 are H; R3 is absent; and R5 is selected from hydroxy and C1-8alkoxy.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T4 is N; T1, T2, and T3 are C; R2 and R3 are H; R5 is absent; and R4 is selected from C1-8alkyl and C1-8alkoxy.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T1 is N; T2, T3, and T4 are C; R3, R4, and R5 are H; and R2 is absent.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T2 is N; T1, T3, and T4 are C; R2, R4, and R5 are H; and R3 is absent.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T3 is N; T1, T2, and T4 are C; R2, R3, and R5 are H; and R4 is absent.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein T4 is N; T1, T2, and T3 are C; R2, R3, and R4 are H; and R5 is absent.
- In one group of embodiments, the invention provides compounds for use of Formula Ib wherein Q is selected from an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three Ra.
- In one group of embodiments, the invention provides compounds of Formula (I'), wherein R2 and R3 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, CO2Rd, CONRdRd, and C(O)Rd, where z is 1, 2, or 3.
- In one group of embodiments, the invention provides compounds of Formula (I'), wherein T2 is N; R2 and R5 are H; R3 is absent; and R4 is C1-8alkoxy, haloC1-8alkoxy, and O(CH2)2C1-8alkyl.
- In one group of embodiments, the invention provides compounds of Formula (I'), wherein T2 is N; R2 and R4 are H; R3 is absent; and R5 is selected from hydroxy and C1-8alkoxy.
- In one group of embodiments, the invention provides compounds of Formula (I'), wherein T4 is N; R2 and R3 are H; R5 is absent; and R4 is selected from C1-8alkyl and C1-8alkoxy.
- In one group of embodiments, the invention provides compounds of Formula (I'), or another group of embodiments of Formula (I') that is disclosed herein, wherein Q is selected from the group consisting of an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three Ra.
-
- In one group of embodiments, the invention provides compounds of Formula (I') wherein at least one z is 1. In yet another group of embodiments, at least one z is 2. In still another group of embodiments, at least one z is 3. No z is 0.
- In certain embodiments, the compounds of Formula (I) and/or (I'), or tautomers or pharmaceutically acceptable salts thereof, are selected from Table 1 below.
Table 1. Compound Structure Name 1 4-(pyridin-3-ylmethoxy)nicotinaldehyde 2 3-(pyridin-3-ylmethoxy)isonicotinaldehyde 3 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)nicotinaldehyde 4 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)picolinaldehyde 5 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde 6 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde 7 3-(imidazo[1,5-a]pyridin-8-ylmethoxy)isonicotinaldehyde 8 2-methoxy-5-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)isonicotinaldehyde 9 8-((3-formylpyridin-2-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide 10 8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide 11 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde 12 2-(2-(imidazo[1,2-a]pyridin-8-yl)ethyl)nicotinaldehyde 13 5-(2-(imidazo[1,2-a]pyridin-8-yl)ethyl)-2-methoxyisonicotinaldehyde 14 5-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde 15 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyrazolo[1,5-a]pyrazine-2-carboxamide 16 5-((2-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 17 2-(imidazo[1,2-a]pyridin-2-ylmethoxy)nicotinaldehyde 18 2-methoxy-5-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3 -yl)methoxy)isonicotinaldehyde 19 2-(imidazo[1,2-a]pyridin-8-ylmethoxy)nicotinaldehyde 20 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methylisonicotinaldehyde 21 3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)isonicotinaldehyde 22 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde 23 3-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)isonicotinaldehyde 24 6-((4-formylpyridin-3-yloxy)methyl)pyrrolo[1,2-a]pyrazine-7-carbonitrile 25 6-((4-formylpyridin-3-yloxy)methyl)pyrrolo[1,2-a]pyrazine-7-carboxamide 26 3-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)isonicotinaldehyde 27 3-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)isonicotinaldehyde 28 2-methoxy-5-((6-oxo-1,6-dihydropyridin-3-yl)methoxy)isonicotinaldehyde 29 2-methoxy-5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)isonicotinaldehyde 30 2-methoxy-5-(oxazol-5-ylmethoxy)isonicotinaldehyde 31 5-((1H-imidazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde 32 5-((1H-imidazol-2-yl)methoxy)-2-methoxyisonicotinaldehyde 33 5-((4H-1,2,4-triazol-3-yl)methoxy)-2-methoxyisonicotinaldehyde 34 5-((1H-tetrazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde 35 5-((1H-pyrazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde 36 5-((1H-pyrazol-4-yl)methoxy)-2-methoxyisonicotinaldehyde 37 2-methoxy-5-(oxazol-4-ylmethoxy)isonicotinaldehyde 38 2-methoxy-5-((2-methylpyridin-3-yl)methoxy)isonicotinaldehyde 39 2-methoxy-5-((4-methylpyridin-3-yl)methoxy)isonicotinaldehyde 40 2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)isonicotinaldehyde 41 2-methoxy-5-((6-methylpyridin-3-yl)methoxy)isonicotinaldehyde 42 2-methoxy-5-(pyridin-3-ylmethoxy)isonicotinaldehyde 43 2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde 44 5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde 45 2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehyde 46 2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde 47 2-methoxy-5-((3-methylpyridin-4-yl)methoxy)isonicotinaldehyde 48 5-((3-bromopyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde 49 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde 52 2-methoxy-5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methoxy)isonicotinaldehyde 53 methyl 2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate 54 2-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)isonicotinaldehyde 55 5-((3-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde 56 5-((6-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde 57 5-((8-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde 58 2-methoxy-5-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde 59 5-((3-(1H-pyrazol-5-yl)imidazo [1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde 60 5-((6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde 61 2-methoxy-5-((8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)isonicotinaldehyde 62 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile 63 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 64 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile 65 5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 66 5-((5-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 70 5-((5-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 71 5-((4-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 74 2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 75 2-methoxy-5-((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 76 5-((5-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 77 2-methoxy-5-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 78 methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate 79 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid 80 2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde 81 6-methyl-3-(quinolin-3-ylmethoxy)picolinaldehyde 82 5-(isoquinolin-7-ylmethoxy)-2-methoxyisonicotinaldehyde 83 3-(isoquinolin-7-ylmethoxy)-6-methylpicolinaldehyde 84 2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde 85 6-methyl-3-((1-methyl-1H-indazol-4-yl)methoxy)picolinaldehyde 86 tert-butyl 4-((2-formyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate 87 5-((1H-indazol-4-yl)methoxy)-2-methoxyisonicotinaldehyde 88 3-((1H-indazol-4-yl)methoxy)-6-methylpicolinaldehyde 89 6-methoxy-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde 90 2-methoxy-5-((1-methyl-1H-indazol-7-yl)methoxy)isonicotinaldehyde 91 6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde 92 6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde 93 3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde 94 6-methyl-3-(quinolin-2-ylmethoxy)picolinaldehyde 95 5-((4-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 96 5-((6-bromoimidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde 97 8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carbonitrile 98 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinonitrile 99 3-(benzo[d]oxazol-4-ylmethoxy)-6-methylpicolinaldehyde 100 8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide 101 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinamide 102 5-((6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde 103 5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde 104 5-((6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde 105 5-((1,5-naphthyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde 106 3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde 107 5-((1H-indazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde 108 6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolinaldehyde 109 3-((3-chloro-1-methyl-1H-indazol-5-yl)methoxy)-6-methylpicolinaldehyde 110 2-methoxy-5-((1-methyl-1H-indazol-5-yl)methoxy)isonicotinaldehyde 111 5-((3-chloro-1-methyl-1H-indazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde 113 3-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-6-methylpicolinaldehyde 114 5-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde 115 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinamide 116 5-((2-chloroquinolin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 117 5-((2-(1H-pyrazol-5-yl)quinolin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 118 2-methoxy-5-(quinoxalin-2-ylmethoxy)isonicotinaldehyde 119 6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde 120 2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde 121 6-methyl-3-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methoxy)picolinaldehyde 122 2-methoxy-5-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methoxy)isonicotinaldehyde 123 5-((7-(1H-pyrazol-3-yl)imidazo [1,5-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde 124 5-((5-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 125 5-((6-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde 127 2-methoxy-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 128 5-((2-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 129 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 130 2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 131 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 132 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 133 5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde 134 5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 135 3-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde 136 6-methyl-3-(pyridin-3-ylmethoxy)picolinaldehyde 137 methyl 8-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate 138 methyl 2-bromo-8-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate 139 3-(imidazo[1,5-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde 140 5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde 142 5-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 143 5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 147 5-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 148 5-((2-(1,3-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 149 5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 150 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 151 2-methoxy-5-((2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 157 5-((2-(4-(1H-pyrazol-3-yl)piperazin-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 158 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde 159 2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehyde 160 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde 161 5-([2,3'-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde 162 2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde 163 2-methoxy-5-((2'-methoxy-[2,3'-bipyridin]-3-yl)methoxy)isonicotinaldehyde 164 methyl 4-(((2-formylpyridin-3-yl)oxy)methyl)benzoate 165 4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid 166 4-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid 167 methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoate 168 methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate 169 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid 170 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid 171 3-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid 172 2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 173 2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 174 2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 175 5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 176 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)picolinaldehyde 177 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde 178 2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 179 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde 180 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde 181 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde 182 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate 183 5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 184 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 186 3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 187 3-(benzyloxy)-5-hydroxyisonicotinaldehyde 188 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde 189 5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 190 5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 191 5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 192 2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1) 194 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde 195 5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 196 5-((2-(1-cyclohexyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 198 5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde 199 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid 200 methyl 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate 201 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid 202 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid 203 3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid 204 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinonitrile 2,2,2-trifluoroacetate 205 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid hydrochloride 206 2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide (2:1) 207 2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 208 2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 209 2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 210 2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 211 2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 212 3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 213 3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 214 3-chloro-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 215 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde 216 3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde 217 3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde - In one group of embodiments, the compound of Formula (I) and/or Formula (I') is selected from:
- 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,
- 2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde,
- 2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehyde,
- 2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde,
- 3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde,
- methyl 2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate,
- 2-methoxy-5-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde,
- 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((5-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid,
- 2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde,
- 2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde,
- tert-butyl 4-((2-formyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate,
- 6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde,
- 6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde,
- 3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde,
- 5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde,
- 3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde,
- 6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolinaldehyde,
- 6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde,
- 2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde,
- 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde,
- 2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-([2,3'-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde,
- 2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methoxy-5-((2'-methoxy-[2,3'-bipyridin]-3-yl)methoxy)isonicotinaldehyde,
- 4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid,
- 4-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid,
- methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoate,
- methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate,
- 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid,
- 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid,
- 3-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid,
- 2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)picolinaldehyde,
- 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde,
- 2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde,
- 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde,
- 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate,
- 5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, 3-(benzyloxy)-5-hydroxyisonicotinaldehyde,
- 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde,
- 5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid,
- 2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1),
- 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde,
- 5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1-cyclohexyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,
- 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid,
- methyl 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate,
- 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid,
- 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid,
- 3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid,
- 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinonitrile 2,2,2-trifluoroacetate,
- 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid,
- 6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid hydrochloride,
- 6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide,
- 2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide (2:1),
- 2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3 -yl)methoxy)isonicotinaldehyde,
- 3-chloro-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde,
- 3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, and
- 3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,
- In one group of embodiments, provided is a pharmaceutical composition comprising a compound of Formula (I') or a tautomer or pharmaceutically acceptable salt thereof.
- In one group of embodiments, provided is a compound in any of the Examples or Tables which is according to Formula (I'), or a compound for use as defined above in any of the Examples or Tables which is according to Formula (I). In another group of embodiments, provided are any combinations of subembodiments as disclosed herein including any combination of elements disclosed herein including the a selection of any single elements.
- The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.
- Also disclosed herein is an intermediate compound used in the preparation of the compounds disclosed herein.
- Also disclosed herein are methods for preparing the compounds disclosed herein.
- For example, Scheme I shows a synthetic route for the synthesis of the compounds of Formula (I) where X is O and Y is CH2. Phenol 1.1 is contacted with intermediate 1.2 in the presence of base under ether forming conditions to give ether 1.3, where Lg represents a leaving group such as a halogen leaving group. Conversely, when X is O and Y is CH2, the compounds of Formula (I) can be prepared using the appropriate starting materials where the OH moiety of intermediate 1.1 is replaced with a leaving group and the Lg group of intermediate 1.2 is replaced with an OH group.
- Scheme II shows an example of a synthetic route for the synthesis of the compounds of Formula (I) where X and Y are CH2. Alkene 2.1 is contacted with alkene 2.2 under metathesis forming conditions in the presence of an appropriate transition metal catalyst. Suitable catalysts include ruthenium catalysts such as Grubbs' catalyst. Product 2.3 is then hydrogenated to give compound 2.4.
- Scheme IV shows an example of synthesis of the compounds of Formula (I) where Q is pyridine-3-yl and Ra heteroaryl. Acid 4.1 is reduced to alcohol 4.2 using known methods such as by forming the anhydride (e.g. treatment with triethylamine and i-butyl chloroformate) followed by reduction with NaBH4. Alcohol 4.2 is converted to chloride 4.3 such as by treatment with thionyl chloride. Coupling of the halide with alcohol 4.4 under ether forming conditions gives the precursor 4.5 that can be functionalized with a variety to heteroaryl Ra groups. For example, 4.5 can be coupled with pyrazole 4.6 under known organometallic coupling conditions (e.g. Pd(PPh3)4) to give 4.7, where PG is a nitrogen protecting group such as a silyl protecting group that can be removed to give the product 4.8.
- One skilled in the art will recognize that in certain embodiments it may be advantageous to use a protecting group strategy. The protecting group can be removed using methods known to those skilled in the art.
- The compounds of the present invention may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts.
- It is understood that in another group of embodiments, any of the above embodiments may also be combined with other embodiments listed herein, to form other embodiments of the invention. Similarly, it is understood that in other embodiments, listing of groups includes embodiments wherein one or more of the elements of those groups is not included.
- Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, preferably in unit dosage form suitable for single administration of a precise dosage. In addition to an effective amount of the active compound(s), the compositions may contain suitable pharmaceutically-acceptable excipients, including adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically. "Pharmaceutically acceptable excipient" refers to an excipient or mixture of excipients which does not interfere with the effectiveness of the biological activity of the active compound(s) and which is not toxic or otherwise undesirable to the subject to which it is administered.
- For solid compositions, conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in water or an aqueous excipient, such as, for example, water, saline, aqueous dextrose, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary excipients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
- For oral administration, the composition will generally take the form of a tablet or capsule, or it may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used excipients such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending excipients. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional excipients for incorporation into an oral formulation include preservatives, suspending agents, thickening agents, and the like.
- Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions or liposomal formulations. The sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
- The pharmaceutical compositions of this invention may also be formulated in lyophilized form for parenteral administration. Lyophilized formulations may be reconstituted by addition of water or other aqueous medium and then further diluted with a suitable diluent prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are isotonic saline solution, 5% dextrose in water, and buffered sodium or ammonium acetate solution. Pharmaceutically acceptable solid or liquid excipients may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Typically, a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating use of the pharmaceutical composition in the treatment of of the indicated disease.
- The pharmaceutical composition may additionally contain one or more other pharmacologically active agents in addition to a compound of this invention.
- Dosage forms containing effective amounts of the modulators are within the bounds of routine experimentation and within the scope of the invention. A therapeutically effective dose may vary depending upon the route of administration and dosage form. The representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, and the time of administration, rate of excretion, drug combination, judgment of the treating physician and severity of the particular disease being treated. The amount of active ingredient(s) will also depend upon the particular compound and other therapeutic agent, if present, in the composition.
- The compounds of the present invention may be useful for increasing tissue oxygenation, when a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof is administered to a subject in need thereof.
- In one group of embodiments, provided is a compound for use in a method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of the above embodiments or a tautomer or pharmaceutically acceptable salt thereof, and further wherein the condition is selected from the group consisting of sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound.
- In one group of embodiments, provided is a compound for use in a method for treating a condition associated with oxygen deficiency as defined above, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound Formula (I) as defined herein.
- The following examples of compounds according to Formula (I') and/or compounds for use according to Formula (I) are offered to illustrate, but not to limit, the claimed invention.
- The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65.
- The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
- Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20°C to about 75°C.
- Referring to the examples that follow, compounds of the present invention were synthesized using the methods described herein, or other methods known in the art.
-
-
- Acetyl chloride (20 mL) was added dropwise to methanol (200 mL) at 0 °C. After the addition, the reaction mixture was stirred at this temp for 15 min and then 4.0 g of the acid was added. The reaction mixture was heated at reflux for 12 h. Methanol was removed to give a residue, which was then carefully neutralized with aq. sat. NaHCO3 and then extracted with EtOAc (3x). The organic layers were combined, dried and evaporated to give the ester as a yellow solid, which was used in the next step without further purification.
-
- A mixture of chloride (300 mg, 1.5 mmol, 1.0 eq), hydroxypyridne (230 mg, 1.5 mmol, 1.0 eq) and potassium carbonate (621 mg, 4.5 mmol, 3.0 eq) were taken in DMF (10 mL) and the reaction mixture was heated at 80 °C for 4 h. Solvent was removed and the crude was purified by column chromatography (Hexane/ EtOAc to EtOAc/ MeOH) to provide the coupled product.
-
- To an ice cold solution of ester (1.5 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH solution (1.5 mL, 2M solution in THF) and the reaction mixture was stirred at this temp for 30 min. Then excess ethyl acetate was added slowly to quench excess LAH. Then water (1mL), 15% NaOH (1mL) and water (3 mL) were added and stirred at rt for 30 min. The clear solution was filtered and the solid was washed with ethyl acetate (3X). The organic layers were combined, dried and evaporated to give the crude alcohol, which was used in the next step without further purification.
-
- To a solution of the above alcohol (1.5 mmol, 1.0 eq) in DCM (15 mL) was added Dess-Martin reagent (2.25 mmol, 454 mg, 1.5 eq) and the reaction mixture was stirred at rt for 1h. Solution was diluted with 25 mL DCM and then a 1:1 mixture of sat. NaHCO3 and sat. Na2S2O3 was added and stirred for 30 min to get two clear layers. Aqueous layer was separated and washed with DCM (3x). Organic layer was dried and evaporated to give a crude product, which was purified by column chromatography (EtOAc/ MeOH). NMR (400 MHz, CDCl3): δ 5.35 (s, 2H), 7.49 (m, 1H), 7.60 (d, 1H), 8.02 (m, 1H), 8.25 (m, 1H), 8.38 (s, 1H), 8.53 (m, 1H), 8.70 (m, 1H) 10.58 (s, 1H); MS: exact mass calculated for C12H10N2O2, 214.07; m/z found, 215 [M+H]+.
-
-
- To a DMF (15 mL) solution of the chloride (300 mg, 1.5 mmol, 1.0 eq) and phenol (230 mg, 1.5 mmol, 1.0 eq) was added K2CO3 (621 mg, 4.5 mmol, 3.0 eq) and the reaction mixture was heated at 80-90 °C for 5 h. Solvent was removed and the residue was purified by column chromatography (EtOAc/ MeOH) to give the alkylation product. MS: exact mass calculated for C15H13N3O3, 283.10; m/z found, 284 [M+H]+.
-
- To a cooled solution of the ester (1.5 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH in THF (1.5 mL, 2.0 M solution in THF, 2.0 eq) and the reaction mixture was stirred at this temperature for 30 min. Excess ethyl acetate was added very slowly followed by water (1.0 mL), 15% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate (3x). Combined organic layers were dried and evaporated to provide the alcohol, which was used in the next step without further purification. MS: exact mass calculated for C14H13N3O2, 255.10; m/z found, 256 [M+H]+.
-
- To a solution of the above alcohol (1.5 mmol, 1.0 eq) in DCM (15 mL) was added Dess-Martin reagent (2.25 mmol, 954 mg, 1.5 eq) and the reaction mixture was stirred at rt for 1h. The reaction was then diluted with 25 mL DCM and then a 1:1 mixture of sat. NaHCO3 and sat. Na2S2O3 was added and stirred for 30 min to get two clear layers. The aqueous layer was separated and washed with DCM (3x). The organic layer was dried and evaporated to give a crude product which was purified by column chromatography (EtOAc/ MeOH). MS: exact mass calculated for C4H11N3O2, 253.09; m/z found, 254 [M+H]+.
-
-
- To a solution of chloride (200 mg, 1.0 mmol, 1.0 eq), and phenol (153 mg, 1.0 mmol, 1.0 eq) in DMF (15 mL) was added K2CO3 (414 mg, 3.0 mmol, 3.0 eq) and the reaction mixture was heated at 80-90 °C for 5 h. Solvent was removed and the residue was purified by column chromatography (EtOAc/ MeOH) to give the alkylation product. MS: exact mass calculated for C15H13N3O3, 283.10; m/z found, 284 [M+H]+.
-
- To a cooled solution of the ester (1.0 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH in THF (4 mmol, 2.0 mL, 2.0 M solution in THF, 4.0 eq) and the reaction mixture was stirred at this temperature for 30 min. Excess ethyl acetate was added very slowly followed by water (1.0 mL), 15% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at rt for 30 min. Filtered and the solid was washed with ethyl acetate (3x). Combined organic layers were dried and evaporated to provide the alcohol, which was used in the next step without further purification. MS: exact mass calculated for C14H13N3O2, 255.10; m/z found, 286 [M+H]+.
-
- To a cooled solution of the ester (1.0 mmol, 1.0 eq) in THF (15 mL) was slowly added LAH in THF (4 mmol, 2.0 mL, 2.0 M solution in THF, 4.0 eq) and the reaction mixture was stirred at this temperature for 30 min. Excess ethyl acetate was added very slowly followed by water (1.0 mL), 15% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at rt for 30 min. Reaction was filtered and the solid was washed with ethyl acetate (3x). Combined organic layers were dried and evaporated to provide the alcohol, which was used in the next step without further purification. MS: exact mass calculated for C14H13N3O2, 255.10; m/z found, 286 [M+H]+.
-
- 4-chloro-3-pyridine aldehyde (1.0 g, 7 mmol, 1.0 eq), 3-hydroxymethyl pyridine (5.4 g, 49.45 mmol, 7 eq) and p-tolunesulfonic acid mon hydrate (1.3 g, 7.0 mmol, 1.0 eq) in benzene (30 mL) were heated using a Dean-Stark trap for 24 h. Solvent was removed and purified by column chromatography to provide the alkylation product. MS: exact mass calculated for C12H10N2O2, 214.22; m/z found, 215 [M+H]+.
-
-
- To a mixture of 6-methoxypyridin-3-ol (25 g, 0.2 mol) and K2CO3 (82.8 g, 0.6 mol) in DMF (250 mL) was added bromomethyl methyl ether (30 g, 0.24 mmol) slowly at rt for a period of 1h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified on silica gel with 25% EtOAc/hexanesas eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 59%) as a colorless oil. LRMS (M+H+) m/z 170.1
-
- To a solution of 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 0.12 mol) in THF was added diisopropylamine (0.24 g, 2.4 mmol). The solution was cooled to -40 °C followed by addition of MeLi (3M/THF, 72mL, 0.216 mol) slowly. The resulting mixture was warmed to 0 °C, stirred at 0 °C for 3 h, cooled back down to -40 °C and added N-formylpiperidine (24mL, 0.216mol). After stirring at -40 °C for 2 h, the mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature was then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture was adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified on silica gel with 25%EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 42%) as a pale yellow oil. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 H), 5.20 (s, 2 H), 3.84 (s, 3 H), 3.48 (s, 3 H).
-
- To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 0.05 mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction was stirred at 50 °C for 30 min, cooled to rt, and diluted with water (100 mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200 mL) three times. The organic layer was dried over Na2SO4 and concentrated to give 5-hydroxy-2-methoxyisonicotinaldehyde (4.2 g, 55%) as a yellow solid. 1H NMR (400 MHz; DMSO) δ= 10.31(s, 1 H), 8.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H).
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (723.6 mg, 4.7 mmol), 8-(chloromethyl)-imidazol[1,2-a] pyridine (785 mg, 4.7 mmol), and K2CO3 (1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at 125 °C for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (500 mg, 38%) as an off-white solid. 1H NMR (400 MHz; DMSO) δ= 10.37 (s, 1 H), 8.58 (d, 1 H), 8.39 (s, 1 H), 8.02 (s, 1 H), 7.61 (s, 1 H), 7.44 (d, 1 H), 6.98 (s, 1 H), 6.93 (t, 1 H), 5.61 (s, 2 H), 3.84 (s, 3 H). LRMS (M+H+) m/z 284.0.
- Examples 6-13 were synthesized according to Example 5.
- 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.15 - 7.09 (m, 1H), 5.29 (s, 2H), 3.94 (s, 3H), 2.51 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.15 - 7.09 (m, 1H), 5.29 (s, 2H), 3.94 (s, 3H), 2.51 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.54 (d, J = 5.7 Hz, 1H), 8.30 (s, 1 H), 8.31 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.78 - 7.63 (m, 3H), 7.07 (d, J = 0.5 Hz, 1H), 5.82 (s, 2H), 3.91 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 8.2, 1.1 Hz, 1H), 7.78 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.60 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.13 (s, 1H), 5.52 (s, 2H), 3.91 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.59 (d, J = 6.0 Hz, 2H), 7.92 (s, 1H), 7.30 (d, J = 6.0 Hz, 2H), 7.06 (s, 1H), 5.16 (s, 2H), 3.84 (s, 3H).
- 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.56 (d, J = 6.7 Hz, 1H), 8.02 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 6.7 Hz, 1H), 6.96 (t, J = 6.9 Hz, 1H), 5.59 (s, 2H), 2.49 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.32 (dd, J = 6.7, 1.3 Hz, 1H), 8.17 (s, 1H), 8.03 (dd, J = 7.2, 1.3 Hz, 1H), 7.76 (s, 1H), 7.11 (s, 1H), 6.94 (t, J = 7.0 Hz, 1H), 5.53 (s, 2H), 4.06 (s, 3H), 3.93 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.14 (s, 1H), 7.89 (d, J = 6.9 Hz, 1H), 7.44 (dd, J = 6.8, 1.1 Hz, 1H), 7.11 (s, 1H), 6.94 (t, J = 6.9 Hz, 1H), 5.67 (s, 2H), 3.92 (s, 3H), 2.80 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 7.35 (dd, J = 7.7, 4.7 Hz, 1H), 7.12 (s, 1H), 6.51 (dd, J = 2.5, 1.8 Hz, 1H), 5.75 (s, 2H), 3.93 (s, 3H).
-
- To a solution of 2-bromonicotinic acid (4.0 g, 20 mmol) and triethylamine (3.34 mL, 24 mmol, 1.2 eq.) in THF (100 mL) was added i-butyl chloroformate (3.12 mL, 24 mmol, 1.2 eq.) at 0 °C. The mixture was stirred at 0 °C for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (1.52 g, 40 mmol, 2 eq.) in water (1.0 mL) at 0 °C. The mixture was stirred for 30 min, added water (3 mL), continued to stir for 2 h, and concentrated to dryness. The crude was purified on silica gel using a mixture of ethylacetate and hexanes as eluent to give (2-bromopyridin-3-yl)methanol (3.4 g, 90%) as a white solid. LRMS (M+H+) m/z 188.0.
-
- To (2-bromopyridin-3-yl)methanol (380 mg, 2 mmol) in DCM (5 mL) was added SOCl2 (1 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give an off-white solid (480 mg), which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (306 mg, 2 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine (crude above, 2 mmol), and K2CO3 (828 mg, 6 mmol, 3 eq.) in DMF (1.0 mL) was heated at 50 °C for 2 h. The mixture was cooled and added to water (50 mL) dropwise. The precipitate was filtered, washed with water, dried under high vacuo to give 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (350 mg, 85%) as an yellow solid. 1H NMR (400 MHz; CDCl3) δ = 10.51 (s, 1 H), 8.42 (dd, 1 H), 8.09 (s, 1 H) 7.91 (d, 1 H), 7.40 (dd, 1 H), 7.15 (s, 1 H), 5.27 (s, 2 H), 3.95 (s, 3 H). LRMS (M+H+) m/z 323.0.
-
- 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (258 mg, 0.8 mmol, 1 equiv), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-ylboronic acid (233 mg, 0.96 mmol, 1.2 equiv), Pd(PPh3)4 (92 mg, 0.08 mmol, 0.1 equiv), K2CO3 (331 mg, 2.4 mmol, 3 equiv) in a round bottom flask were added dioxane (8 mL) and water (2 mL). The mixture was heated 2 h at 90 °C, cooled, filtered, and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (208 mg, 79%) as a white solid. 1H NMR (400 MHz; CDCl3) δ = 10.54 (s, 1 H), 8.85 (d, 1 H), 8.18 (d, 1 H) 8.03 (s, 1 H), 7.73 (d, 1 H), 7.56 (dd, 1 H), 7.21 (s, 1 H), 6.60 (d, 1H), 5.79 (s, 2 H), 5.27 (s, 2 H), 4.01 (s, 3 H), 3.65 (t, 2 H), 0.88 (t, 2 H), 0.05 (s, 9 H). LRMS (M+H+) m/z 441.2.
-
- To 2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (120 mg, 0.27 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (1.0 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N2 gas and the precipitate was collected. The solid was washed with acetonitrile and EtOAc and dried under high vacuo to give 5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde dihydrochloride (100 mg, 96%) as a white solid. 1H NMR (400 MHz; DMSO, 80 °C) δ = 10.27 (s, 1 H), 8.68 (br, 1 H), 8.32 (br, 1 H), 8.22 (s, 1 H), 7.82 (br, 1 H), 7.57 (br, 1 H), 7.00 (br, 2 H), 5.75 (s, 2 H), 3.89 (s, 3 H). LRMS (M+H+) m/z 311.1.
- Examples 15-22 were synthesized according to Example 14.
- 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 8.41 (dd, J = 4.7, 1.8 Hz, 1H), 8.09 (s, 1H), 7.91 (dd, J = 7.6, 1.6 Hz, 1H), 7.39 (dd, J = 7.6, 4.8 Hz, 1H), 7.15 (s, 1H), 5.27 (s, 2H), 3.95 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.15 (s, 1H), 5.22 (s, 2H), 3.95 (d, J = 0.8 Hz, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.75 (dd, J = 9.0, 2.1 Hz, 2H), 8.11 (s, 1H), 7.88 (t, J = 2.1 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.13 (s, 1H), 6.43 (d, J = 1.9 Hz, 1H), 5.30 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 7.94 (s, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.57 (s, 1H), 7.29 (dd, J = 7.8, 4.8 Hz, 2H), 7.10 (s, 1H), 5.24 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.42 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.68 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (dd, J = 7.9, 1.6 Hz, 1H), 7.84 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.03 (s, 1H), 6.32 (d, J = 1.9 Hz, 1H), 5.09 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.78 (s, 1H), 7.48 - 7.44 (m, 2H), 7.41 - 7.34 (m, 3H), 7.28 (dd, J = 7.8, 4.8 Hz, 1H), 6.99 (s, 1H), 5.12 (s, 2H), 3.80 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 7.99 (dd, J = 7.8, 1.6 Hz, 1H), 7.80 (s, 1H), 7.40 (dd, J = 7.8, 4.8 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.28 - 7.23 (m, 1H), 7.23 - 7.18 (m, 1H), 7.06 (s, 1H), 4.98 (s, 2H), 3.89 (s, 3H), 2.13 (s, 3H).
- 1H NMR(400 MHz, CDCl3) δ 10.31 (s, 1H), 8.71 (dd, J = 4.8, 1.4 Hz, 1H), 8.28 (dd, J = 5.0, 1.9 Hz, 1H), 7.96 (dd, J = 7.8, 0.9 Hz, 1H), 7.82 (s, 1H), 7.74 (dd, J = 7.3, 1.9 Hz, 1H), 7.41 (dd, J = 7.8, 4.8 Hz, 1H), 7.09 - 7.03 (m, 2H), 5.14 (s, 2H), 3.96 (s, 3H), 3.89 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.54 (s, 1H), 8.84 (dd, J = 4.8, 1.6 Hz, 1H), 8.14 (dd, J = 7.9, 1.6 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.21 (s, 1H), 6.60 (d, J = 1.8 Hz, 1H), 5.79 (s, 2H), 5.27 (s, 2H), 4.01 (s, 3H), 3.66-3.59 (m, 2H), 0.92 - 0.80 (m, 2H), 0.00 (s, 9H).
- 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.79 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.63 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.14 (s, 1H), 5.42 (s, 2H), 3.94 (s, 3H).
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (352 mg, 2.29 mmol, 1 eq.), methyl 5-(chloromethyl)nicotinate hydrochloride (506 mg, 2.29 mmol, 1eq.), and K2CO3 (1.26 g, 9.16 mmol, 4 eq.) in DMF (8.0 mL) was heated at 60 °C for 3 h. The mixture was cooled and added into water (50 mL) dropwise. The precipitate was filtered, washed with water, and dried to give methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (350 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.42 (t, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.15 (s, 1H), 5.29 (s, 2H), 4.01 (s, 3H), 3.95 (s, 3H). LRMS (M+H+) m/z 303.1.
-
- To 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (96 mg, 0.32 mmol, 1 eq.) in a mixture of MeOH/THF (1/3, 8.0 mL) was added NaOH (3 N, 1.7 mL, 5.1 mmol, 16 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid (86 mg, 93%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 10.34 (s, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.42 (t, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.02 (s, 1H), 5.44 (s, 2H), 3.86 (s, 3H). LRMS (M+H+) m/z 289.1.
- Examples 26-35 were synthesized according to the procedure in Example 25.
- 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.46 (dd, J = 4.3, 0.6Hz, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.50 - 7.40 (m, 2H), 5.33 (s, 2H), 3.95 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.16 (d, J = 8.2Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 1.8 Hz, 2H), 5.32 (s, 2H), 2.61 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.38 (dd, J = 4.3, 1.2 Hz, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.42 - 7.32 (m, 2H), 5.26 (s, 2H).
- 1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.64 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.16 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 5.38 (s, 2H), 3.96 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.11 (s, 1H), 8.02 (d, J= 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 5.26 (s, 2H), 3.93 (s, 3H).
- 1H NMR (400 MHz, DMSO) δ 13.21 - 12.87 (br, 1H), 10.45 (s, 1H), 8.82 (s, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.1 Hz, 1H), 7.63 - 7.46 (m, 2H), 5.52 (s, 2H).
- 1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 9.99 (s, 1H), 7.87 (s, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.60 - 7.50 (m 2H), 7.38 - 7.30 (m, 2H), 5.16 (s, 2H).
- 1H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 10.23 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.68 (dd, J = 8.6, 4.4 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 5.41 (s, 2H).
- 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.97 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 6.89 (s, 1H), 5.05 (s, 2H), 3.69 (s, 3H).
- The title compound was prepared as for Example 34 above.
- 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.40 (s, 1H), 8.23 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.4, 7.3 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.6, 1H), 5.58 (s, 2H), 2.58 (s, 3H), 1.75 (s, 9H).
-
- To a mixture of 1-methyl-1H-indazole-4-carbaldehyde (180 mg, 1.12 mol) in THF (10 mL) was added NaBH4 (85 mg, 2.24 mmol) at r.t. The reaction mixture was stirred at r.t. for 1 h, acidified to pH 3, and extracted with EtOAc. The combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, filtered, and concentrated to give a crude solid (191 mg), which was used for next step without further purification.
-
- To (1-methyl-1H-indazol-4-yl)methanol (191 mg) in DCM (5 mL) was added SOCl2 (2 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give an off-white solid (210 mg), which was used for next step without further purification.
-
- A mixture of 2-hydroxy-5-methoxyisonicatinaldehyde (170 mg, 1.12 mmol), 4-(chloromethyl)-1-methyl-1H-indazole (1.12 mmol), and K2CO3 (618 mg, 4.48 mmol) is refluxed in CH3CN (20 mL) for 2 h. The mixture is filtered and the solid is washed with DCM. The filtrate is concentrated and purified on silica gel using a mixture of EtOAc and MeOH as eluent to give 5-methoxy-2-((1-methyl-1H-indazol-4-yl)methoxy)isonicatinaldehyde as a white solid.
- Examples 37- 45 were prepared according to Example 36.
- 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.48 - 7.38 (m, 2H), 7.22 (dd, J = 6.0, 0.8 Hz, 1H), 7.10 (s, 1H), 5.55 (s, 2H), 4.13 (s, 3H), 3.91 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.98 (d, J = 0.9 Hz, 1H), 7.75 (dd, J = 8.3, 0.8 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.18 (dd, J = 8.3, 1.3 Hz, 1H), 5.37 (s, 2H), 4.10 (s, 3H), 2.58 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.02 (s, 1H), 7.77 (dd, J = 8.1, 1.0 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.38 (dd, J = 7.0, 1.0 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.12 (dd, J = 8.1, 7.0 Hz, 1H), 5.56 (s, 2H), 4.35 (s, 3H), 2.60 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.52 (d, J = 5.7 Hz, 1H), 8.48 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.77 - 7.66 (m, 4H), 7.27 (d, J = 8.9 Hz, 1H), 5.86 (s, 2H), 2.55 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 8.18 (d, J = 7.3 Hz, 2H), 7.63 (dd, J = 8.1, 1.0 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 0.5 Hz, 1H), 5.65 (s, 2H), 3.92 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.15 (d, J = 2.1 Hz, 1H), 9.05 (dd, J = 4.2, 1.6 Hz, 1H), 8.52 (d, J = 1.1 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.5, 4.2 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 5.50 (s, 2H), 2.62 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 5.34 (s, 2H), 4.11 (d, J = 0.5 Hz, 3H), 2.59 (s, 3H).
- 1H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.96 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (d, J =8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.80 (dd, J = 8.4, 7.1 Hz, 1H), 7.61 (dd, J = 8.6, 4.2 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 5.78 (s, 2H), 2.49 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.94 (dd, J = 4.3, 1.5 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 14.1 Hz, 1H), 8.13 (s, 2H), 7.68 (dd, J = 8.3, 7.2 Hz, 1H), 7.61 (d, J = 6.7 Hz, 1H), 7.47 (dd, J = 8.6, 4.3 Hz, 1H), 7.02 (s, 1H), 5.56 (s, 2H), 3.84 (s, 3H).
-
- To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1 eq.; refer to example 14) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) was added TBSCl (19.2 g, 150.7 mmol, 1.2 eq.) at rt. The mixture was stirred at rt for 1 h and diluted with a mixture of water (100 mL) and EtOAc (300 mL). The organic layer was washed with NH4Cl(sat.) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) as a colorless oil. LRMS (M+H+) m/z 302.0.
-
- A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)2 (23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N2 for 5 min and added Pd(PPh3)4 (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120 °C for 2 h under N2, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. LRMS (M+H+) m/z 249.1.
-
- Methylmagnesium bromide (3M/ether, 41.0 mL, 123.4 mmol) was added to a stirred solution of 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82.25 mmol) in THF (100.0 mL) at -78 °C. The reaction mixture was warm to rt, quenched with aqueous citric acid solution, and extracted with EtOAc (50 mL) twice. The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc/hexanes as eluent to give 1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (12.9 g, 59%) as a colorless oil. LRMS (M+H+) m/z 266.2.
-
- 1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g, 40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for next step without further purification. LRMS (M+H+) m/z 321.1.
-
- To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 966.4 mg, 3.02 mmol, 1 eq.) in EtOH (10 mL) was added methylhydrazine (1.0 mL) at rt. The mixture was heated at 80 °C for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of regio-isomers (420 mg; 46% for 2 steps). LRMS (M+H+) m/z 304.2.
-
- To a mixture of 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine and 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine (420 mg, 1.38 mmol) in MeOH (20 mL) was added HCl (4 N, 2.0 mL). The mixture was stirred at rt for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (187 mg, 72%) and (2-(1-methyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 21%) as white solids. Data for 2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: 1H NMR (400 MHz; CDCl3) 8.58 (d, 1 H), 7.91 (d, 1 H), 7.46 (s, 1H), 7.30 (dd, 1 H), 6.36 (s, 1 H), 4.62 (d, 2 H), 3.83 (s, 3 H), 2.1 (t, 1 H). LRMS (M+H+) m/z 190.1; data for (2-(1-methyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: 1H NMR (400 MHz; CDCl3) 8.60 (d, 1 H), 7.70 (d, 1 H), 7.47 (s, 1H), 7.22 (dd, 1 H), 6.99 (s, 1 H), 5,91 (t, 1 H), 4.68 (d, 2 H), 4.01 (s, 3 H). LRMS (M+H+) m/z 190.1
-
- To (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (182 mg, 0.96 mmol) in DCM (5 mL) was added SOCl2 (1.5 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine (236 mg) as an off-white solid, which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (147 mg, 0.96 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride (236 mg, 0.96 mmol, 1 eq.), and K2CO3 (532 mg, 3.85 mmol, 3 eq.) in DMF (3.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (232.5 mg, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.77 (dd, J = 4.7, 1.7 Hz, 1H), 8.03 (dd, J = 7.9, 1.7 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (d, J = 0.4 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H). LRMS (M+H+) m/z 325.1.
- 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.77 (dd, J = 4.7, 1.7 Hz, 1H), 8.03 (dd, J = 7.9, 1.7 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (d, J = 0.4 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H).
- The title compound was prepared according to the procedure in Example 46.
- 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.66 (dd, J = 4.7, 1.3 Hz, 1H), 8.11 (s, 1H), 8.03 (dd, J = 7.8, 1.0 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J = 2.0 Hz, 1H), 5.73 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).
-
- To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), Zn (CN)2 (71 mg, 0.62 mmol, 2.0 equiv), Pd(PPh3)4 (72 mg, 0.06 mmol, 0.2 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 15 min at 125 °C in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (71 mg, 84%) as a white solid. 1H NMR (400 MHz; CDCl3) δ = 10.54 (s, 1 H), 8.86 (d, 1 H), 8.22 (s, 1 H), 8.20 (d, 1 H), 7.74 (dd, 1 H), 6.37 (s, 1H)5.52 (s, 2 H), 4.04 (s, 3 H). LRMS (M+H+) m/z 270.1.
-
- To TEA hydrochloride salt (123 mg, 0.89 mmol, 4 equiv.) and 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (70 mg, 0.26 mmol, 1 equiv.) in chlorobenzene (5.0 mL) was added NaN3 (48 mg, 0.89 mmol, 4 equiv.) at rt. The mixture was heated to 110 °C for 2 h, cooled to rt, and added water (5.0 mL). The precipitate was filtered and washed with EtOAc and water and dried under high vacuo to give 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde as a white solid. 1H NMR (400 MHz; DMSO) δ = 10.23 (s, 1 H), 8.61 (d, 1 H), 8.16 (s, 1 H), 8.10 (d, 1 H), 7.38 (dd, 1 H), 6.96 (s, 1H)5.73 (s, 2 H), 3.83 (s, 3 H). LRMS (M+H+) m/z 313.0.
-
- To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (98 mg, 0.47 mmol, 1.5 equiv), Pd(PPh3)4 (70 mg, 0.06 mmol, 0.2 equiv), K2CO3 (171 mg, 1.24 mmol, 4 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 30 min at 125 °C in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(4-methyl-l-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 87%) as a colorless oil. LRMS (M+H+) m/z 409.2.
-
- To 2-methoxy-5-((2-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 0.27 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (1.0 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N2 gas and basified to pH 9. The aqueous solution was extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated. The crude was purified on silica gel using a mixture of MeOH and DCM as eluent to give 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (40 mg, 46%) as a white solid. 1H NMR (400 MHz; CDCl3) δ = 10.45 (s, 1 H), 8.76 (d, 1 H), 8.07 (br, 1 H), 8.05 (s, 1H), 7.53 (s, 1 H), 7.40 (dd, 1 H), 7.13 (s, 1 H), 5.52 (br, 2 H), 3.98 (s, 3 H). LRMS (M+H+) m/z 325.1.
-
- To a mixtire of POCl3 (0.73 mL, 7.85 mmol, 3.8 eqiv.) and DMF (0.6 g, 8.16 mmol, 4.0 equiv.) in THF was added 1,2-dihydroisoquinolin-3(4H)-one at 0 °C in portions for 5 min. The mixture was continued to stir at 0 °C for 1 h and poured into a mixture of 2 N NaOH (20 mL), ice (20 g), and toluene (20 mL). The organic phase was separated and the aqueous layer was extracted with toluene one more time. The combined organic layer was washed with water, dried over Na2SO4, and concentrated to half of its volume at low temperature in vacuo. To this mixture was added 2 N H2SO4 (20 mL) under vigorous stirring followed by ground KMnO4 in portions. The mixture was continued to stir for another 4 h. The organic phase was separated, dried over Na2SO4, and concentrated to give 3-chloroisoquinoline-4-carbaldehyde (220 mg, 50% pure) as a oil, which was used for next step without further purification. LRMS (M+H+) m/z 192.0.
-
- To 3-chloroisoquinoline-4-carbaldehyde (220 mg, crude) in THF (10 mL) was added NaBH4 (155 mg, 4.08 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, acidified to pH 3, and extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, filtered, and concentrated to give a crude solid. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloroisoquinolin-4-yl)methanol (92 mg, 24% for three steps). LRMS (M+H+) m/z 194.0.
-
- To (3-chloroisoquinolin-4-yl)methanol (92 mg, 0.48 mmol) in DCM (5 mL) was added SOCl2 (mL) at rt The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give an off-white solid (120 mg), which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (73 mg, 0.48 mmol, 1 eq.), 3-chloro-4-(chloromethyl)isoquinoline (crude above, 0.48 mmol), and K2CO3 (265 mg, 1.92 mmol, 4 eq.) in DMF (2.0 mL) was heated at 60 °C for 1 h. The mixture was cooled, filtered, concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes to give 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (22 mg, 14%) as an yellow solid. 1H NMR (400 MHz; CDCl3) δ = 10.19 (s, 1 H), 9.05 (s, 1 H), 8.23 (s, 1 H) 8.06 (d, 1 H), 7.98 (d, 1 H), 7.76 (t, 1 H), 7.63 (t, 1 H), 7.01 (s, 1H), 5.72 (s, 2 H), 3.87 (s, 3 H). LRMS (M+H+) m/z 329.1.
-
- To a mixture of 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (18 mg, 0.05 mmol, 1 equiv), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-ylboronic acid (20 mg, 0.08 mmol, 1.5 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.2 equiv), K2CO3 (30 mg, 0.22 mmol, 4 equiv) in a 5 mL microwave tube were added DMF (2 mL). The mixture was heated 30 min at 125 °C in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 38%) as a white solid. LRMS (M+H+) m/z 491.1.
-
- To 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 0.02 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (0.1 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N2 gas and basified to pH 9. The aqueous solution was extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated. The crude was purified on silica gel using MeOH and DCM as eluent to give 5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 83%) as a white solid. 1H NMR (400 MHz; CDCl3) δ = 10.17 (s, 1 H), 9.25 (s, 1 H), 8.18 (s, 1 H), 8.05 (d, 1 H), 7.99 (d, 1 H), 7.73 (t, 1 H), 7.60-7.68 (m, 2 H), 7.03 (s, 1 H), 6.70 (d, 1 H), 5.85 (s, 2 H), 3.85 (s, 3 H). LRMS (M+H+) m/z 361.1.
-
- To a cold solution of 3-ethoxycarbonylpyridine (25 g, 165.4 mmol, 1 eq) in DCM was slowly added mCPBA (70% wt, 198.5 mmol) and the reaction mixture was stirred at rt overnight. Reaction was cooled and diluted with DCM and then neutralized with slow addition of sat. NaHCO3. Aqueous layer was washed with DCM (3X) and the combined organic layer was dried and evaporated to give a residue, which was purified by column chromatography (EtOAc/ MeOH) to give 3-ethoxycarbonylpyridine N-oxide (13.6 g). MS: exact mass calculated for C8H9NO3, 167.06; m/z found, 168 [M+H]+.
-
- To a solution of 3-ethoxycarbonylpyridine N-oxide in 330 mL of DCM were added trimethylsilyl cyanide (TMSCN) (11.0 g, 65.9 mmol, 1.0 eq) and dimethylcarbamoyl chloride (7.1 g, 65.9 mmol, 1.0 eq) and the reaction mixture was stirred at rt for 2 days. Then 10% K2CO3 was slowly added to make the reaction mixture basic. Organic layer was separated, dried and evaporated to provide the crude, which was purified by column chromatography to provide compounds A (5.7 g) and B (3.5 g).
-
- To a solution of ethyl 2-cyano-3-pyridinecarboxylate (2.5 g) and conc. HCl (5 mL) in 150 mL ethanol was added 10% Pd/C (wet, 250 mg) and the reaction mixture was hydrogenated using a hydrogen balloon and stirred for 12 h. The reaction was filtered through celite and ethanol was evaporated to give ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid which was used in the next step without further purification.
- A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60 °C oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat. NaHCO3 solution. Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H]+.
-
- To a cold solution of lithium aluminum hydride (1.62 g, 42,4 mmol, 4.0 eq) in THF (50 mL) was added the crude ethyl imidazo[1,5-a]pyridine-8-carboxylate (2.7 g, 14.2 mmol, 1.0 eq) and the reaction mixture was heated at reflux for 2 h. The reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowly added. Solution was diluted with excess EtOAc and stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate. Organic layers were combined, dried and solvent was removed to give crude imidazo[1,5-a]pyridine-8-methanol, which was purified by column chromatography (EtOAc/ Hexane). MS: exact mass calculated for C8H8N2O, 148.06; m/z found, 149 [M+H]+.
- To a solution of imidazo[1,5-a]pyridine-8-methanol (800 mg) in chloroform (50 mL) was slowly added thionyl chloride (10 mL) and the reaction mixture was stirred at rt for 8 h. Chloroform was removed and the residue was then taken in toluene and toluene was evaporated (3x) to give a solid, which was used in the next step without further purification. MS: exact mass calculated for C8H7ClN2, 166.03; m/z found, 167 [M+H]+.
-
- To a solution of chloride (1.25 mmol, 1.0 eq), and hydroxynicotinaldehyde (1.25 mmol, 1.0 eq) in DMF (10 mL) is added K2CO3 (3.0 eq) and the reaction mixture was heated at 80-90 °C for 5 h. Solvent is removed and the residue is purified by column chromatography (EtOAc/ MeOH).
- The title compound was prepared according to the procedure in Example 51.
- 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 6.87 (t, J = 8.1 Hz, 1H), 6.62 (t, J = 6.8 Hz, 1H), 5.37 (s, 2H), 3.92 (s, 3H).
-
- To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol, 1 eq.) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol, 1.5 eq.) at 0-5 °C portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5 °C for 15 min, added chloromethyl methyl ether (15.5 g, 0.19 mol, 1.2 eq.), stirred at 0-5 °C for another 20 min, and quenched with NH4Cl(sat.) solution. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated , and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. 1H NMR (400 MHz; CDCl3) 7.97 (d, 1 H), 7.35 (dd, 1 H), 6.70 (d, 1 H), 5.12 (s, 2 H), 3.91 (s, 3 H), 3.51 (s, 3 H). LRMS (M+H+) m/z 170.1
-
- To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol, 1 eq.) and diisopropylamine (507 uL, 3.6 mmol, 0.02 eq.) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol, 1.8 eq.) at -40 °C. Upon the completion of addition, the mixture was warmed to 0 °C, continued to stir at 0 °C for 3 h, cooled back down to -40 °C and added DMF (24.7 mL, 0.32 mol, 1.8 eq.) slowly. The mixture was then stirred at -40 °C for 1 h, quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL), warmed to rt, and added water (200 mL). The pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The aqueous layer was extracted with EtOAc (300 mL) twice. The combined organic layers were dried over Na2SO4 and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1 H), 6.92 (s, 1 H), 5.64 (s, 1 H), 5.20 (s, 2 H), 3.84 (s, 3 H), 3.48 (s, 3 H). LRMS (M+H+) m/z 198.1
-
- To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). The reaction was stirred at 50 °C for 1 h, cooled to rt, and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%) as a pale yellow solid. 1H NMR (400 MHz; DMSO) δ= 10.31 (s, 1 H), 8.03 (s, 1 H), 6.89 (s, 1 H), 3.80 (s, 3 H). LRMS (M+H+) m/z 154.0.
-
- To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 1.03 g, 3.22 mmol, 1 eq.; refer to Example 46) in EtOH (10 mL) was added isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). The mixture was heated at 80 °C for 2 h, cooled, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHCO3(sat) (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) as pale yellow oils. Data for 2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: 1H NMR (400 MHz, CDCl3) δ 8.67 (dd, J = 4.7, 1.5 Hz, 1H), 8.0 (d, J= 7.8 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 7.8, 4.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 4.67 (s, 2H), 4.55 (sep, J = 6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 218.1 Data for (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: 1H NMR (400 MHz, CDCl3) δ 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.55 (d, J= 2.4 Hz, 1H), 7.23 (dd, J = 7.6, 4.8 Hz, 1H), 6.99 (dd, J = 8.0, 6.5 Hz, 1H), 6.07 (t, J = 7.6 Hz, 1H), 4.67 (d, J = 7.6 Hz, 2H), 4.58 (sep, J = 6.7 Hz, 1H), 1.60 (d, J = 6.7 Hz, 1H). LRMS (M+H+) m/z 218.1
-
- To (2-(1-iospropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (560 mg, 2.58 mmol) in DCM (10 mL) was added SOCl2 (3.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg) as an off-white solid, which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K2CO3 (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg, 65%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J = 6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
-
- 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (980 mg, 2.78 mmol, 1 eq.) in HCl (6 N, 9.2 mL, 20 eq.) solution was frozen at -78 °C. The mixture was lyophilized O/N to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde bis-hydrochloride as a yellow solid. 1H NMR (400 MHz, D2O) δ 8.85 (dd, J = 5.7, 1.3 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.12 (dd, J = 8.1, 5.7 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.46 (s, 1H), 6.65 (d, J = 2.1 Hz, 1H), 6.09 (s, 1H), 5.09 (s, 2H), 4.24 (sep, J = 6.6 Hz, 1H), 4.04 (s, 3H), 1.26 (d, J = 6.6 Hz, 7H). LRMS (M+H+) m/z 353.1.
- 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.10 (s, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (hept, J = 6.6 Hz, 1H), 3.91 (s, 3H), 1.49 (d, J = 6.6 Hz, 6H).
- Examples 57-62 were prepared according to the procedure in Example 55.
- 1H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 10.23 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.68 (dd, J = 8.6, 4.4 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 5.41 (s, 2H).
- 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8.04 (dd, J = 7.9, 1.3 Hz, 1H), 7.93 (s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.41 (d, J = 1.9 Hz, 1H), 5.17 (s, 2H), 4.23 (t, J = 7.4 Hz, 2H), 3.92 (s, 3H), 1.80 (sex, , J = 7.4 Hz, 2H), 0.81 (t, J = 7.4 Hz, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 7.97 (dd, J = 7.9, 1.4 Hz, 1H), 7.91 (s, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.05 (s, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.17 (q, J = 8.6 Hz, 2H), 5.11 (s, 2H), 3.85 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 (dd, J = 7.9, 1.4 Hz, 1H), 7.87 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.02 (s, 1H), 6.42 (d, J = 1.9 Hz, 1H), 6.11 (tt, J = 56.0, 4.4 Hz, 1H), 5.11 (s, 2H), 4.67 (td, J = 13.4, 4.4 Hz, 2H), 3.83 (s, 3H).
- 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8.47 (dd, J = 4.4, 1.0 Hz, 1H), 8.32 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.49 (td, J = 8.3, 4.6 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 5.15 (s, 2H), 4.65 (sep, J= 6.6 Hz, 1H), 1.49 (d, J = 6.6 Hz, 6H).
- 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.75 (dd, J = 4.7, 1.3 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.48 (dd, J = 7.9, 4.8 Hz, 1H), 7.31 (d, J = 8.6Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.38 (d, J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.64 (sep, J = 6.6 Hz, 1H), 2.61 (s, 3H), 1.49 (d, J = 6.6 Hz, 6H).
- 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.68 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (s, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.01 (s, 1H), 6.30 (d, J = 1.8 Hz, 1H), 5.05 (s, 2H), 4.77 (quin, J = 8.4 Hz, 1H), 3.82 (s, 3H), 2.74 - 2.56 (m, 2H), 2.32-2.15 (m, 2H), 1.87 - 1.73 (m, 1H), 1.72 - 1.59 (m, 1H).
- 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.68 (dd, J = 4.7, 1.5 Hz, 1H), 7.96 (dd, J = 7.9, 1.2 Hz, 1H), 7.81 (s, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.02 (s, 1H), 6.28 (d, J = 1.8 Hz, 1H), 5.05 (s, 2H), 4.10 (quin, J = 7.6 Hz, 1H), 3.83 (s, 3H), 1.96 - 1.83 (m, J = 2.9 Hz, 4H), 1.83 - 1.68 (m, 2H), 1.68 - 1.45 (m, 2H), 1.33 - 1.06 (m, 2H).
- 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.77 (dd, J = 4.7, 1.5 Hz, 1H), 8.04 (dd, J = 7.9, 1.2 Hz, 1H), 7.90 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.38 (d, J = 1.9 Hz, 1H), 5.15 (s, 2H), 4.74 (quin, J = 7.5 Hz, 1H), 3.92 (s, 3H), 2.23 - 1.85 (m, 6H), 1.63 - 1.51 (m, 2H).
-
- To 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (300 mg, 0.84 mmol, 1 equiv) in a vial was added HCl (6 N, 1 mL, 6 mmol). The mixture was concentrated, dried under vaccum at 60 °C O/N, cooled to rt, and dissolved in NaOH (3 N, 5 mL), filtered, and washed with with EtOAc twice. The pH of the aqueous layer was adjust to pH 6-7, filtered, and purified by RP-HPLC (Gemini 21.2 x 150 mm) with a mixture of CH3CN and water (0.1% HCOOH) as eluent to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde formate (82.5 mg, 31%) as an yellow solid. 1H NMR (400 MHz, D2O) δ 8.56 (d, J = 7.1 Hz, 1H), 8.32 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 72 Hz, 1H), 7.81 (t, J = 2.1 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.27 (s, 1H), 6.68 (s, 1H), 5.94 (s, 1H), 5.32 (s, 2H). LRMS (M+H+) m/z 270.1.
-
- To 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) in CH3CN (10 mL) was added sodium 2-chloro-2,2-difluoroacetate (84.5 mg, 0.56 mmol, 1.5 eq.). The mixture was stirred at rt O/N and concentrated. The crude was purified on silica gel using 10% MeOH/DCM as eluent to give 2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde (6.0 mg, 5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.61 (s, 2H), .7.44 (t, J = 60.0 Hz, 1H), 7.24-7.27 (m, 2H), 6.79 (t, J = 7.0 Hz, 1H), 5.63 (s, 2H). LRMS (M+H+) m/z 320.0.
- The title compound was prepared according to the procedure in Example 67.
- 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.80 (d, J = 3.7 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 7.33 (t, J = 72.8 Hz, 1H), 6.37 (d, J = 1.7 Hz, 1H), 5.21 (s, 2H), 4.67 (sep, J = 6.6 Hz, 1H), 1.50 (d, J = 6.6 Hz, 6H).
-
-
- To a mixture of 3-bromoisonicotinic acid (2.5 g, 12.37 mmol, 1eq.) and TEA (3.44 mL, 24.75 mmol, 2.0 eq.) in THF (100 mL) was added methyl chloroformate (1.2 mL, 14.85 mmol, 1.2 eq.) at 0 °C. The mixture was stirred at 0 °C for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (0.95 g, 24.75 mmol, 2 eq.) in water (1.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, quenched with NH4Cl (aq) solution, extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-bromopyridin-4-yl)methanol (1.2 g, 52%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.37 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 4.9 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H), 2.3 (t, J = 5.5 Hz, 1H). LRMS (M+H+) m/z 188.0.
-
- To a mixture of (3-bromopyridin-4-yl)methanol (150 mg, 0.8 mmol, 1 eq.), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (226 mg, 0.96 mmol, 1.2 eq.), Pd(dppf)Cl2 (58 mg, 0.08 mmol, 0.1 eq.), and K2CO3 (331 mg, 3.0 mmol, 3 eq.) in a RB flask were added dioxane (6 mL) and water (2 mL). The mixture was heated at 100 °C for 2 h, cooled, filtered, and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methanol (75 mg, 43%) as a yellow oil. LRMS (M+H+) m/z 218.1.
-
- (3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methanol (75 mg, 0.35 mmol) in SOCl2 (5 mL) was heated at 60 °C for 30 min and concentrated. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give a brown solid (95 mg), which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (79 mg, 0.52 mmol, 1.5 eq.), 4-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (crude above, 0.35 mmol), and K2CO3 (145 mg, 1.05 mmol, 3 eq.) in DMF (10.0 mL) was heated at 100 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on RP-HPLC (Gemini 21.2 x 150 mm) twice using a mixture of CH3CN/water (0.1% HCOOH) as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (6.0 mg, 5%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1 H), 7.52 (d, J = 1.7 Hz, 1H), 6.96 (s, 1H), 6.15 (d, J = 1.8 Hz, 1H), 4.87 (s, 2H), 4.06 (sep, J = 6.6 Hz, 1H), 3.75 (s, 3H), 1.31 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
- The title compound was prepared according to the procedure in Example 69.
- 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.71 (dd, J = 4.8, 1.5 Hz, 1H), 8.02 (dd, J = 7.8, 1.5 Hz, 1H), 7.96 (dt, J = 7.9, 1.9 Hz, 1H), 7.90 (s, 1H), 7.49 - 7.42 (m, 2H), 7.10 (s, 1H), 5.21 (s, 2H), 3.91 (s, 3H).
-
- To a mixture of 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (100 mg, 0.37 mmol, 1 equiv) and K2CO3 (153.2 mg, 1.11, 3.0 eq.) in DMF (5 mL) was added 1-bromo-2-methoxyethane (154.3 mg, 1.11 mmol, 3.0 eq.). The mixture was stirred at rt O/N, filtered, concentrated, and purified on silica gel using 10% MeOH/DCM as eluent to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde (6.0 mg, 5%) as an yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.08 (d, J = 6.8 Hz, 1H), 8.06 (s, 1H), 7.60 (dd, J = 6.8, 1.2 Hz, 2H), 7.27 (dd, J = 6.9, 1.0 Hz, 1H), 7.09 (s, 1H), 6.78 (t, J = 6.9 Hz, 1H), 5.58 (s, 2H), 4.35 (dd, J = 5.4, 3.9 Hz, 2H), 3.66 (dd, J = 5.4, 3.9 Hz, 2H), 3.36 (s, 3H). LRMS (M+H+) m/z 328.1.
- The title compound was prepared according to the procedure in Example 71.
- 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (dd, J = 4.7, 1.5 Hz, 1H), 8.04 (dd, J = 7.9, 1.2 Hz, 1H), 7.87 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.16(s, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.65 (sep, J = 6.6 Hz, 1H), 4.42 (t, J = 4.8 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.44 (s, 3H), 1.49 (d, J = 6.6 Hz, 6H).
-
- To a solution of 3-chloropyrazine-2-carboxylic acid (2.0 g, 12.70 mmol, 1.0 eq.) and TEA (3.50 mL, 25.40 mmol, 2.0 eq.) in THF (50 mL) was added methyl chloroformate (1.2 mL, 15.20 mmol, 1.2 eq.) at 0 °C. The mixture was stirred at 0 °C for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (0.97 g, 25.40 mmol, 2 eq.) in water (1.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, quenched with NH4Cl(aq) solution, and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloropyrazin-2-yl)methanol (400 mg, 22%) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.58 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 4.84 (s, 2H). LRMS (M+H+) m/z 145.1.
-
- To a mixture of (3-chloropyrazin-2-yl)methanol (200 mg, 1.4 mmol, 1 eq.), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (393 mg, 1.67 mmol, 1.2 eq.), Pd(dppf)Cl2 (102 mg, 0.14 mmol, 0.1 eq.), and K2CO3 (580 mg, 4.2 mmol, 3 eq.) in a RB flask were added dioxane (6 mL) and water (2 mL). The mixture was heated at 100 °C for 1 h, cooled to rt, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanol (110 mg, 36%) as a yellow oil. LRMS (M+H+) m/z 219.1.
-
- 3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methanol (75 mg, 0.35 mmol) in SOCl2 (5 mL) was heated at 60 °C for 30 min and concentrated. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give a brown solid (95 mg), which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (110 mg, 0.60 mmol, 1.2 eq.), 2-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyrazine hydrochloride (crude above, 0.5 mmol, 1 eq.), and K2CO3 (207 mg, 1.50 mmol, 3 eq.) in DMF (15.0 mL) was heated at 100 °C for 30 min. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((3-(1-isopropyl1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde (12.0 mg, 68%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.06 (s, 1H), 6.49 (d, J = 1.9 Hz, 1H), 5.32 (s, 2H), 4.68 (sep, J = 6.6 Hz, 1H), 3.89 (s, 2H), 1.48 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 354.1.
-
- To 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (55 mg, 0.17 mmol, 1 equiv) in MeOH (15 mL) was added SOCl2 (5.0 mL). The mixture was heated to reflux O/N, concentrated, and neutralized to pH 8-9 with NaHCO3(sat.) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate (51.5 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.67 (dd, J = 4.6, 1.5 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 8.03 (s, 1H), 7.51 (dd, J = 8.0, 4.6 Hz, 1H), 7.06 (s, 1H), 5.60 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H). LRMS (M+H+) m/z 303.1.
-
- Methylmagnesium bromide (3M/ether, 2.0 mL, 5.65 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (1180 mg, 3.76 mmol, 1 eq.) in THF (10.0 mL) at -78 °C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)ethanone (776 mg, 63%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.54 (dd, J = 8.0, 4.0 Hz, 1H), 6.95 (s, 1H), 6.23 (s, 1H), 5.59 (s, 2H), 4.22 - 4.04 (m, 4H), 3.90 (s, 3H), 2.79 (s, 3H).LRMS (M+H+) m/z 331.1.
-
- Methylmagnesium bromide (3M/ether, 0.25 mL, 0.75 mmol, 3.0 eq.) was added to a stirred solution of 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (82 mg, 0.25 mmol, 1 eq.) in THF (5.0 mL) at -78 °C. After addition, the reaction mixture was warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (38 mg, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 7.7, 1.6 Hz, 1H), 7.84 (dd, J = 7.7, 1.5 Hz, 1H), 7.74 (s, 1H), 7.18 (dd, J = 7.7, 4.7 Hz, 1H), 6.84 (s, 1H), 6.01 (s, 1H), 5.27 (s, 2H), 4.07 - 3.88 (m, 4H), 3.82 (s, 3H), 1.55 (s, 6H). LRMS (M+H+) m/z 347.1.
-
- To 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (30 mg, 0.087 mmol, 1 eq.) in a RB flask was added HCl (6 N, 3.0 mL). The mixture was warmed to 40 °C O/N, cooled to rt, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (10.2 mg, 99%) as a pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.46 (dd, J = 4.7, 1.6 Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J = 7.8, 1.5 Hz, 1H), 7.24 (dd, J = 7.8, 4.7 Hz, 1H), 7.05 (s, 1H), 5.37 (s, 2H), 3.85 (s, 3H), 1.57 (s, 6H). LRMS (M+H+) m/z 303.1.
-
- To a solution of 6-(benzyloxy)pyridin-3-ol (2.0 g, 10 mmol, 1 eq.) in DMF (20 mL) was added NaH (60% in mineral oil; 0.6 g, 15 mmol, 1.5eq.) at 0-5 °C portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5 °C for 15 min, added chloromethyl methyl ether (0.88 g, 11 mmol, 1.1 eq.), stirred at 0-5 °C for another 20 min, and quenched with NH4Cl(sat.) solution. The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-(benzyloxy)-5-(methoxymethoxy)pyridine (2.1 g, 87%) as a colorless oil. LRMS (M+H+) m/z 246.1
-
- To 2-(benzyloxy)-5-(methoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H2 (15 psi), stirred at rt for 45 min, filtered, and concentrated to give 5-(methoxymethoxy)pyridin-2-ol (1.35 g, quantitative yield) as a pale yellow solid. LRMS (M+H+) m/z 156.1
-
- To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and K2CO3 (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added 1-bromo-2-methoxyethane (3.61 g, 26.1 mmol, 3eq.). The mixture was heated at 60 °C for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 3.0 Hz, 1H), 7.35 (ddd, J = 8.9, 3.0, 1.0 Hz, 1H), 6.76 (dd, J = 8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48-4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H). LRMS (M+H+) m/z 214.1.
-
- To a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (1.34 g, 6.3 mol, 1 eq.) and diisopropylamine (17.5 uL, 0.13 mmol, 0.02 eq.) in THF (50 mL) was added methyl lithium (1.6 M/THF, 7 mL, 11.3 mol, 1.8 eq.) at -40 °C. Upon the completion of addition, the mixture was warmed to 0 °C, continued to stir at 0 °C for 3 h, cooled back down to -40 °C, and added DMF (0.83 mL, 11.3 mol, 1.8 eq.) slowly. The mixture was then stirred at -40 °C for 1 h, quenched with a mixture of HCl (12 N, 12 mL) and THF (28 mL), warmed to rt, and added water (20 mL). The pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The aqueous layer was extracted with EtOAc (30 mL) twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give a mixture of 2-(2-methoxyethoxy)-5-(methoxymethoxy)isonicotinaldehyde and 2-(2-methoxyethoxy)-5-(methoxymethoxy)nicotinaldehyde (5/1, 1.27 g, 83.6%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.23 (s, 1H), 7.16 (s, 1H), 5.27 (s, 2H), 4.46 (dd, J = 5.4, 3.9 Hz, 2H), 4.14 (q, J = 7.1 Hz, 1H), 3.77 - 3.71 (m, 2H), 3.56 (s, 3H), 3.46 (s, 3H) and 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.18 (d, J = 3.2 Hz, 1H), 7.85 (d, J = 3.1 Hz, 1H), 5.16 (s, 2H), 4.64 - 4.57 (m, 2H), 3.85 - 3.79 (m, J = 5.4, 4.0 Hz, 2H), 3.50 (s, 3H), 3.46 (s, 3H); LRMS (M+H+) m/z 242.1.1
-
- To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (1.27 g, 5.29 mol) in THF (5 mL) was added HCl (3 N, 4 mL). The reaction was stirred at 50 °C for 1 h, cooled to rt, and diluted with water (5 mL). The mixture was neutralized to pH 7-8 with solid K2CO3 and the aqueous layer was extracted with EtOAc (100 mL) twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (630 mg, 60%) and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde (120 mg, 11%). Data for 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde: 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 9.50 (s, 1H), 8.07 (s, 1H), 7.02 (s, 1H), 4.51 - 4.39 (m, 2H), 3.81 - 3.72 (m, 2H), 3.47 (s, 3H). LRMS (M+H+) m/z 198.1. Data for and 5-hydroxy-2-(2-methoxyethoxy)nicotinaldehyde: 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 7.99 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 7.18 - 7.07 (br, 1H), 4.54 (dd, J = 5.4, 3.7 Hz, 2H), 3.84 (dd, J = 5.4, 3.7 Hz, 2H), 3.49 (s, 3H). LRMS (M+H+) m/z 198.1
-
- A mixture of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (125 mg, 0.63 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride salt (120 mg, 0.63 mmol, 1 eq.), and Cs2CO3 (410 mg, 1.26 mmol, 2 eq.) in DMF (3.0 mL) was heated at 60 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (59 mg, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.59 (dd, J = 4.7, 1.6 Hz, 1H), 7.87 (dd, J = 7.9, 1.3 Hz, 1H), 7.73 (s, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 7.9, 4.8 Hz, 1H), 7.00 (s, 1H), 6.25 (d, J = 1.9 Hz, 1H), 5.02 (s, 2H), 4.26 (dd, J = 5.4, 3.9 Hz, 2H), 3.80 (s, 3H), 3.57 (dd, J = 5.4, 3.9 Hz, 2H), 3.28 (s, 3H).LRMS (M+H+) m/z 387.1.
- The title compound was prepared according to the procedure in Example 77.
- 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.74 (dd, J = 4.7, 1.5 Hz, 1H), 8.07 (d, J = 3.3 Hz, 1H), 7.98 (dd, J = 7.9, 1.2 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 7.9, 4.8 Hz, 1H), 6.41 (d, J = 1.9 Hz, 1H), 5.04 (s, 2H), 4.62 - 4.51 (m, 2H), 3.96 (s, 3H), 3.82 - 3.76 (m, 2H), 3.45 (s, 3H).
-
- To a mixture of NaH (60% in mineral oil) (2.77 g, 69.25 mmol, 2.5 eq.) in DMF (40.0 mL) was added benzyl alcohol (6.6 g, 61.0 mmol, 2.2 eq.) at 0 °C. The mixture was stirred at 0 °C for 10 min, added 3,5-dichloroisonicotinonitrile (4.8 g, 27.7 mmol, 1 eq.), continued to stir at 0 °C for 30 min, gradually warm to rt, stirred at rt O/N, and quenched with NH4Cl(sat.) solution. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-bis(benzyloxy)isonicotinonitrile (4.94 g, 56%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 2H), 7.58-7.30 (m, 10H), 5.33 (s, 4H). LRMS (M+H+) m/z 317.1
-
- To a mixture of 3,5-bis(benzyloxy)isonicotinonitrile (2.5 g, 7.9 mmol, 1 eq.) and K2CO3 (4.37 g, 31.6 mmol, 4 eq.) in DMSO (10 mL) was added H2O2 (30% in water, 2.0 mL) at rt. The mixture was stirred at rt O/N and added water (50 mL). The solid was collected and dried to give 3,5-bis(benzyloxy)isonicotinamide (2.2 g, 83%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 2H), 7.59 - 7.33 (m, 10H), 5.83 (s, 2H), 5.25 (s, 4H), 4.81 (s, 2 H). LRMS (M+H+) m/z 335.1
-
- To 3,5-bis(benzyloxy)isonicotinamide (1.6 g, 4.79 mmol) in THF (30 mL) was added Cp2ZrCl (3.7 g, 14.4 mmol, 3 eq.) at rt. The mixture was stirred at rt for 2 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-bis(benzyloxy)isonicotinaldehyde (580 mg, 38%) and (3,5-bis(benzyloxy)pyridin-4-yl)methanol (710 mg, 46%) as white solids. Data for aldehyde 1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.13 (s, 2H), 7.51 - 7.22 (m, 10H), 5.21 (s, 4H); LRMS (M+H+) m/z 320.1. Data for alcohol 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 2H), 7.58 - 7.34 (m, 10H), 5.22 (s, 4H), 4.87 (s, 1H).; LRMS (M+H) m/z 322.1.
-
- To a solution of (3,5-bis(benzyloxy)pyridin-4-yl)methanol (910 mg, 2.83 mmol) and imidazole (385 mg, 5.66 mmol) in DMF (10.0 mL) was added TBSCl (513 mg, 3.4 mmol) at rt. The mixture was stirred at rt for 1 h and diluted with a mixture of water (10 mL) and EtOAc (40 mL). The organic layer was washed with NH4Cl(sat.) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 3,5-bis(benzyloxy)-4-((tert-butyldimethylsilyloxy)methyl)pyridine (728 mg, 59%) as an off-white solid. LRMS (M+H+) m/z 436.3.
-
- To 3,5-bis(benzyloxy)-4-((tert-butyldimethylsilyloxy)methyl)pyridine (720 mg, 1.66 mmol, 1 eq.) in a mixture of EtOAc/EtOH (5/2, 28 mL) was added Pd/C (400.0 mg). The mixture was charged with H2 (60 psi), stirred at rt for 2 h, filtered, and concentrated to give 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 2H), 4.91 (s, 2H), 0.73 (s, 9H), -0.00 (s, 6H). LRMS (M+H) m/z 256.1.
-
- A mixture of 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol (100 mg, 0.39 mmol, 2 eq.) and Cs2CO3 (381 mg, 1.17 mmol, 3 eq.) in DMF (15 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (53 mg, 0.39 mmol, 1 eq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (36 mg, 27%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (dt, J = 33.0, 16.5 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.21 (dd, J = 7.8, 4.8 Hz, 1H), 6.10 (d, J = 1.8 Hz, 1H), 4.84 (s, 2H), 4.68 (s, 1H), 4.44 (sep, 6.6 Hz, 1H), 1.24 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 341.1
-
- To 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (26 mg, 0.076 mmol, 1 eq.) in CH3CN (10 mL) was added MnO2 (66 mg, 0.76 mmol, 10eq.). The mixture was heated to 46 °C with stirring O/N, cooled to rt, filtered, and concentrated to give 3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 10.35 (s, 1H), 8.70 (dd, J = 4.7, 1.5 Hz, 1H), 8.11 (s, 1H), 7.89 (dd, J = 7.9, 1.1 Hz, 1H), 7.80 (s, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 6.27 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.61 (sep, J = 6.6 Hz, 1H), 1.41 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 339.1
- The title compound was prepared according to the procedure in Example 79.
- 1H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 10.41 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.39 - 7.28 (m, 5H), 5.18 (s, 2H).
-
- To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135 °C for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135 °C for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.4 Hz, 2H), 6.76 (t, J = 2.4 Hz, 1H), 3.88 (s, 6H).LRMS (M+H+) m/z 140.1.
-
- To a solution of 3,5-dimethoxypyridine (3.6 g, 25.90 mmol, 1 eq.) in THF (80 mL) was added BuLi (3M/hexanes, 13.0 mL, 38.85 mmol, 1.5 eq.) at -20 °C. The mixture was warmed to 0 °C, stirred at 0 °C for 30 min, cooled back down to -78 °C, and added DMF (3.8 g, 51.8 mmol, 2 eq.). The mixture was gradually warmed to 0 °C, quenched with NH4Cl(sat.) solution, and diluted with EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxyisonicotinaldehyde (2.7 g, 62%) as a yellow solid. LRMS (M+H+) m/z 168.1.
-
- To a solution of 3,5-dimethoxyisonicotinaldehyde (2.7 g, 16.16 mmol, 1 eq.) in DCM (100 mL) was added AlCl3 (4.31 g, 32.32 mmol, 2.0 eq.) at rt. The mixture was reflux O/N, cooled to rt, and added into ice (200 g). The aqueous layer was extracted with DCM three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-hydroxy-5-methoxyisonicotinaldehyde (420 mg, 17%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.96 (s, 1H), 10.26 (s, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 3.84 (s, 3H). LRMS (M+H+) m/z 154.1.
-
- A mixture of 3-hydroxy-5-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (54 mg, 0.20 mmol, 1 eq.), and K2CO3 (110 mg, 0.80 mmol, 4 eq.) in DMF (2.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde (30 mg, 43%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.65 (dd, J = 4.7, 1.1 Hz, 1H), 8.13 (s, 1H), 8.11 (dd, J = 7.9, 1.1 Hz, 1H), 7.96 (s, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.37 (dd, J = 7.9, 4.8 Hz, 1H), 6.29 (d, J = 1.7 Hz, 1H), 5.11 (s, 2H), 4.55 (sep, J = 6.6 Hz, 1H), 3.95 (s, 3H), 1.40 (d, J = 6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
-
- To 5-hydroxy-2-methoxyisonicotinaldehyde (1.0 g, 6.54 mmol, 1.0 eq.) in toluene (50.0 mL) were added ethane-1,2-diol (10.0 mL) and PTSA (248 mg, 1.31 mmol, 0.2 eq.). The mixture was heated to reflux O/N, cooled to rt, neutralized to pH 8, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 76%) as an off-white solid. LRMS (M+H+) m/z 198.1.
-
- A mixture of 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 4.97 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine hydrochloride (1.2 g, 4.93 mmol, 1 eq.) and K2CO3 (2.7 g, 19.88 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.21 g, 66%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 4.7, 1.9 Hz, 1H), 7.83 (dd, , J = 7.6, 1.9 Hz, 1H), 7.74 (s, 1H), 7.25 (dd, J = 7.6, 4.8 Hz, 1H), 6.86 (s, 1H), 6.10 (s, 1H), 5.09 (s, 2H), 4.07 - 3.93 (m, 4H), 3.82 (s, 3H). LRMS (M+H+) m/z 367.0.
-
- A mixture of 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.1 g, 3.0 mmol, 1 eq.), Zn (CN)2 (704 mg, 6.0 mmol, 2.0 eq.), and Pd(PPh3)4 (346 mg, 0.3 mmol, 0.2 eq.) in DMF (10 mL) was heated at 125 °C for 2 h under N2. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (820 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.6 Hz, 1H), 8.12 (dd, J = 8.0, 0.7 Hz, 1H), 7.88 (s, 1H), 7.60 (dd, J = 8.0, 4.7 Hz, 1H), 6.95 (s, 1H), 6.16 (s, 1H), 5.37 (s, 2H), 4.18 - 4.00 (m, 4H), 3.92 (s, 3H). LRMS (M+H+) m/z 314.1.
-
- To 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (150 mg, 0.48 mmol, 1 eq.) in a mixture of EtOH/water (5/1, 12 mL) was added NaOH (192 mg, 4.8 mmol, 10 eq.). The mixture was heated to reflux O/N, partially concentrated, added ice, and acidified to pH 3 with HCl(conc.). The solid was collected and dried to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (145 mg, 91%) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.38-8.48 (br, 1H), 8.28-8.35 (br, 1H), 7.76 (s, 1H), 7.50-7.70 (br, 1H), 6.81 (s, 1H), 6.04 (s, 1H), 5.50-5.64 (br, 2H), 4.03 - 3.87 (m, 3H), 3.75 (s, 3H). LRMS (M+H+) m/z 333.0.
-
- To a mixture of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinic acid (145 mg, 0.44 mmol, 1 eq.) and EDCI.HCl (169 mg, 0.88 mmol, 2 eq.) in DMF (3.0 mL) was added DIEA (146 uL, 0.88 mmol, 2 eq.). The mixture was stirred at rt for 1 h and purified by RP-HPLC (Gemini 21.2 x 150 mm) using a mixture of CH3CN and water to isolate the urea intermediate. The fractions were concentrated and dissolved in EtOH (5.0 mL). To this mixture was added hydrazine (0.5 mL) at rt. The mixture was stirred at rt for 1 h, partially concentrated, and diluted with water (10 mL). The solid was collected, washed with water, and dried to give 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinohydrazide (97 mg, 64% for two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.85 (s, 1H), 7.51 (dd, J = 8.0, 4.6 Hz, 1H), 6.95 (s, 1H), 6.24 (s, 1H), 5.80 (s, 2H), 4.20 - 4.06 (m, 4H), 3.90 (s, 3H). LRMS (M+H+) m/z 347.1.
-
- To a mixture of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinohydrazide (90 mg, 0.26 mmol, 1 eq.) and AcOH (0.4 mL) in dioxane (2.0 mL) was added CH(OMe)3 (0.4 mL). The mixture was sealed and heated at 110 °C for 1 h, cooled to rt, and added isopropyl amine (0.4 mL). The mixture was re-sealed, heated at 110 °C O/N, concentrated, and purified on RP-HPLC (Gemini 21.2 x 150 mm) using a mixture of CH3CN and water as eluent to give 4-(1,3-dioxolan-2-yl)-5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (68 mg, 66%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 4.7, 1.2 Hz, 1H), 8.41 (s, 1H), 8.24 (dd, J = 8.0, 1.2 Hz, 1H), 7.76 (s, 1H), 7.45 (dd, J = 8.0, 4.7 Hz, 1H), 6.90 (s, 1H), 6.17(s, 1H), 5.61 (s, 2H), 5.30 (sep, J = 6.7 Hz, 1H), 4.17 - 4.02 (m, 4H), 3.88 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). LRMS (M+H+) m/z 398.2.
-
- To 4-(1,3-dioxolan-2-yl)-5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (60 mg, 0.15 mmol, 1 eq.) in a RB flask was added HCl (6 N, 2.0 mL). The mixture was warmed to 40 °C O/N, cooled to rt, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (52.2 mg, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) 8 10.35 (s, 1H), 8.62 (dd, J = 4.6, 1.2 Hz, 1H), 8.33 (s, 1H), 8.11 (dd, J = 8.0, 1.2 Hz, 1H), 7.98 (s, 1H), 7.40 (dd, J = 8.0, 4.7 Hz, 1H), 6.99 (s, 1H), 5.62 (s, 2H), 5.28 (sep, J = 6.7 Hz, 1H), 3.82 (s, 3H), 1.46 (d, J = 6.7 Hz, 6H). LRMS (M+H+) m/z 354.1.
-
- Ethylmagnesium bromide (3M/ether, 1.53 mL, 4.60 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (960 mg, 3.07 mmol, 1 eq.) in THF (15.0 mL) at -78 °C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (611 mg, 58%) as a colorless oil. LRMS (M+H+) m/z 345.1.
-
- 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (600 mg, 1.74 mmol) in dimethoxy-N,N-dimethylmethanamine (10.0 mL) was heated to reflux O/N. The mixture was concentrated to give (E)-1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one, which was used for next step without further purification. LRMS (M+H+) m/z 400.2.
-
- To (E)-1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one (crude, 230 mg, 0.58 mmol, 1 eq.) in EtOH (5 mL) was added isopropylhydrazine hydrochloride (128 mg, 1.16 mmol, 2 eq.) at rt. The mixture was heated at 80 °C for 2 h, cooled to rt, concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO3(sat) (10.0 mL) solution. The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(1,3-dioxolan-2-yl)-5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (48 mg, 20% for two steps). 1H NMR (400 MHz, CDCl3) δ 8.75 (dd, J = 4.7, 1.4 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.49-7.44 (m, 2H), 6.91 (s, 1H), 6.11 (s, 1H), 4.85-5.01 (m, 2H), 4.30 - 3.98 (m, 5H), 3.88 (s, 3H), 1.94 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H), 1.39 (d, J = 6.7 Hz, 3H). LRMS (M+H+) m/z 411.2.
-
- To 4-(1,3-dioxolan-2-yl)-5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (41 mg, 0.1 mmol, 1 eq.) in a RB flask was added HCl (6 N, 2.0 mL). The mixture was warmed to 40 °C O/N, cooled to rt, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (33.3 mg, 99%) as an pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.71 (dd, J = 4.7, 1.6 Hz, 1H), 7.99 (dd, J = 7.9, 1.5 Hz, 1H), 7.76 (s, 1H), 7.40 (dd, J = 7.1, 4.7 Hz, 1H), 7.39 (s, 1H), 7.01 (s, 1H), 4.86-4.99 (m, 2H), 4.12 (sep, J = 6.7, 1H), 3.82 (s, 3H), 1.86 (s, 3H), 1.40 (d, J = 767 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H).LRMS (M+H+) m/z 367.1.
- The title compound was prepared according to the procedure in Example 83.
- 1H NMR (400 MHz, CDCl3) 8 10.18 (s, 1H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 7.9, 4.9 Hz, 1H), 6.90 (s, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.34 (s, 1H), 5.04 (s, 2H), 4.24 - 4.16 (m, 2H), 3.94 - 3.85 (m, 2H), 3.70 (s, 3H).
-
- Into a 25-mL round-bottom flask, was placed a solution of pyridine-2,6-dicarboxylic acid (1 g, 5.98 mmol, 1.00 equiv) in methanol (12.5 mL). Sulfuric acid (2.5 mL) was added to the reaction mixture. The resulting solution was stirred overnight at 70°C, and then it was quenched by the addition of 10 mL of water. The pH value of the solution was adjusted to 7 with sodium carbonate. The resulting solution was extracted with 2x25 mL of dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.95 g (81%) of 2,6-dimethyl pyridine-2,6-dicarboxylate as a white solid
-
- Into a 100-mL round-bottom flask, was placed a solution of 2,6-dimethyl pyridine-2,6-dicarboxylate (950 mg, 4.87 mmol, 1.00 equiv) in a solvent mixture of methanol (33.2 mL) and dichloromethane (14.2 mL). NaBH4 (185 mg, 5.02 mmol, 1.00 equiv) was added to the reaction mixture in several batches at 0°C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 50 mL of NH4Cl (aq.). The resulting solution was extracted with 2x50 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) as eluent to yield 750 mg (92%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate as a white solid.
-
- Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (300 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). 4-(Dimethoxymethyl)pyridin-3-ol (304.2 mg, 1.80 mmol, 1.00 equiv),and triphenylphosphane (615 mg, 2.34 mmol, 1.30 equiv) was added to the reaction mixture. This was followed by the addition of DIAD (473.1 mg, 2.34 mmol, 1.30 equiv) dropwise at 0°C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 10 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1) as eluent to yield 340 mg (60%) of methyl 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylate as a white solid.
-
- Into a 100-mL round-bottom flask, was placed methyl 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylate (310 mg, 0.97 mmol, 1.00 equiv) and sodium hydroxide (117 mg, 2.93 mmol, 3.00 equiv) in a solvent mixture of methanol (10 mL), water (10 mL) and tetrahydrofuran (10 mL). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solution was extracted with 3x20 mL of isopropal/DCM(1/3) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 230 mg (78%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylic acid as a white solid.
-
- Into an 8-mL sealed tube, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylic acid (150 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3.5 h at 45°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column,5um,19∗150mm,; mobile phase, water with 0.05%TFA and MeCN (10% MeCN up to 35% in 4 min, up to 100% in 1 min,down to 10% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 49 mg (38%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-2-carboxylic acid as a light yellow solid. LC-MS-PH-GBT-ZL-HS-19-0 (ES, m/z): 259 [M+1]+ H-NMR-PH-GBT-ZL-HS-19-0 (300 MHz, DMSO, ppm): 10.52 (s, 1H), 8.92 (s, 1H), 8.52(d, J=4.8 Hz, 1H), 8.09 (m, 2H), 7.95 (m, 1H), 7.76 (d, J=4.8 Hz, 1H), 5.61 (s, 2H).
-
- To 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (862 mg, 2.66 mmol, 1 equiv) suspened in water (5.0 mL) was added HCl (6 N, 4.43 mL, 26.6 mmol, 10 eq.). Once the mixture turned into a homogeneous solution, it was frezee at -78 °C to an solid and pump under high vaccum O/N. The yellow solid was continued to pump at 45 °C for 20 h, dissolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (180 mg, 44% based on 50% recovered of SM) as a white solid. 1H NMR (400 MHz, DMSO at 90 °C) δ 10.14 (s, 1H), 8.63 (s, 1H), 8.09-8.03 (br, 1H), 7.56-7.50 (br, 2H), 7.42-7.35 (br, 1H), 6.70 (s, 1H), 5.39 (s, 2H), 2.18 (s, 3H). LRMS (M+H+) m/z 311.1.
-
- To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (10 mL) was added ethyl 2-hydrazinylacetate hydrochloride (338 mg, 2.18 mmol, 2.0 eq.). The mixture was heated at 80 °C for 2 h, cooled to rt, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO3(sat) (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (212 mg, 74%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 4.7, 1.6 Hz, 1H), 7.97 (dd, J= 7.8, 1.4 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 7.8, 4.8 Hz, 1H), 6.56 (d, J = 1.9 Hz, 1H), 5.21 (s, 2H), 4.79 (d, J = 5.8 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.54 (t, J = 6.0 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H). LRMS (M+H+) m/z 262.1
-
- To ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.70 mmol) in DCM (10 mL) was added SOCl2 (3.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg) as an off-white solid, which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (107mg, 0.70 mmol, 1 eq.), ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg, 0.70 mmol, 1 eq.), and K2CO3 (386 mg, 2.8 mmol, 4 eq.) in DMF (6.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (261 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.69 (d, J = 3.8 Hz, 1H), 8.02 (s, 1 H), 8.01 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 7.6, 4.0 Hz, 1H), 7.13 (s, 1H), 6.53 (d, J = 1.6 Hz, 1H), 5.30 (s, 2 H), 5.28 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). LRMS (M+H+) m/z 397.1.
-
- To ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.46 mmol, 1 eq.) in a mixture of MeOH/THF (1/5, 12.0 mL) was added NaOH (2N, 2.3 mL, 4.6 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid (135.1 mg, 80%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.71 (d, J = 4.7 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 7.9, 4.9 Hz, 1H), 7.13 (s, 1H), 6.56 (d, J = 1.7 Hz, 1H), 5.31 (s, 2H), 5.14 (s, 2H), 3.91 (s, 3H). LRMS (M+H+) m/z 369.1.
- Examples 88 and 89 were prepared according to example 87 above.
- 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 8.05 (dd, J = 7.9, 1.4 Hz, 1H), 7.99 (s, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.12 (s, 1H), 6.41 (d, J = 1.9 Hz, 1H), 5.21 (s, 2H), 4.55 (t, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.62 (s, 3H), 3.00 (t, J = 7.1 Hz, 2H).
- 1H NMR (400 MHz, CDC13) δ 10.33 (s, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 (dd, J = 7.9, 1.5 Hz, 1H), 7.83 (s, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 7.9, 4.8 Hz, 1H), 7.02 (s, 1H), 6.33 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.49 (t, J = 6.5 Hz, 2H), 3.81 (s, 3H), 2.94 (t, J = 6.5 Hz, 2H).
-
- To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (5 mL) was added hydrazine (140 mg, 4.36 mmol, 4 eq.). The mixture was heated at 80 °C for 2 h, cooled, concentrated, and purified on silica gel using EtOAc as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (282 mg, 90%) as a white solid. LRMS (M+H+) m/z 290.1
-
- To a mixture of 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (140 mg, 0.48 mmol, 1 eq.) and Cs2CO3 (312 mg, 0.96 mmol, 2 eq.) in DMF (3 mL) was added methyl 3-bromopropanoate (122 mg, 0.73 mmol, 1.5 eq.). The mixture was stirred at rt for 6 h, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (110 mg, 61%). LRMS (M+H+) m/z 376.1.
-
- To methyl 3-(3-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate in MeOH (10 mL) was added HCl (2 N, 1.2 mL, 10 eq.). The mixture was stirred at rt for 4 h, concentrated, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give methyl 3-(3-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (51 mg, 67%) as an oil. LRMS (M+H+) m/z 262.1.
-
- To methyl 3-(3-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (51 mg, 0.20 mmol) in DCM (5 mL) was added SOCl2 (1.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg) as an off-white solid, which was used for next step without further purification.
-
- A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg, 0.20 mmol, 1 eq.), and K2CO3 (100 mg, 10.32 mmol, 4 eq.) in DMF (5.0 mL) was heated at 70 °C for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (88 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3)δ 10.50 (s, 1H), 8.65 (dd, J = 4.7, 0.9 Hz, 1H), 8.09 (s, 1H), 8.02 (dd, J = 7.8, 0.8 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J = 2.3 Hz, 1H), 5.71 (s, 2H), 4.46 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.69 (s, 3H), 2.91 (t, J = 6.6 Hz, 2H). LRMS (M+H+) m/z 397.1.
-
- To methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (72 mg, 0.18 mmol, 1 eq.) in a mixture of MeOH/THF (1/6, 6.0 mL) was added NaOH (3 N, 0.6 mL, 1.8 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid (53.4 mg, 78%) as a white solid. 1H NMR (400 MHz, CDCl3)δ 10.42 (s, 1H), 8.57 (d, J= 4.6 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J= 7.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 7.9, 4.6 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J = 2.3 Hz, 1H), 5.64 (s, 2H), 4.42 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 2.86 (t, J = 6.1 Hz, 2H). LRMS (M+H+) m/z 383.1.
-
- Into a 250-mL round-bottom flask, was placed a solution of 6-methylpyridine-3-carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mL). N-Bromosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AIBN (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to yield 5 g (37%) of 6-(bromomethyl)pyridine-3-carbonitrile as a beige solid.
-
- Into a 250-mL round-bottom flask, was placed a solution of 6-(bromomethyl)pyridine-3-carbonitrile (3 g, 15.23 mmol, 1.00 equiv) in CH3CN (100 mL). Potassium carbonate (4.24 g, 30.68 mmol, 2.00 equiv) and 4-(dimethoxymethyl)pyridin-3-ol (2.83 g, 16.73 mmol, 1.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 50°C, and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.4 g (32%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile as a red solid.
-
- Into an 8-mL vial, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile (100 mg, 0.35 mmol, 1.00 equiv) in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 5 h at 45°C, and then it was concentrated under vacuum. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column,5um,19∗150mm,; mobile phase, Water and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min,down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 8 mg (10%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carbonitrile as a white solid. LC-MS-PH-GBT-ZL-HS-13-0: (ES, m/z):258 [M+1+18]+. H-NMR-PH-GBT-ZL-HS-13-0: (300MHz, DMSO, ppm): 10.48 (s, 1H), 9.06 (s, 1H), 8.80(s, 1H), 8.47 (m, 2H),7.94 (d, J=8.1Hz, 1H), 7.65(d, J=5.1Hz, 1H), 5.69(s, 2H).
- Into a 100-mL round-bottom flask, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile (1 g, 3.51 mmol, 1.00 equiv) in water (30 mL). Sodium hydroxide (1.4 g, 35.00 mmol, 10.00 equiv) was added to the reaction. The resulting solution was stirred for 4 h at 90oC. The pH value of the solution was adjusted to 4-5 with hydrogen chloride (aq. 3 mol/L). The resulting solution was extracted with 3x200 ml of ethyl acetate. The aqueous layer was extracted again with 3x200 ml of tetrahydrofuran. The combined organic layers were concentrated under vacuum. This resulted in 1 g (94%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid as a yellow solid.
-
- Into an 8-mL vial, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid (100 mg, 0.33 mmol, 1.00 equiv) in a solvent mixture of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at 40°C, and then it was concentrated under vacuum. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5um,19∗150mm; mobile phase, water (0.05%HCl) and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min,down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220nm. This resulted in 30 mg (31%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carboxylic acid hydrochloride as a white solid. The compound exhibited a melting point of 192-194°C. LC-MS-PH-GBT-ZL-HS-14-0: (ES, m/z):259 [M+1]+ / 277 [M+1+18]+. H-NMR-PH-GBT-ZL-HS-14-0: (300MHz, DMSO, ppm): 13.42 (s, 1H), 10.48 (s, 1H), 9.03(s, 1H), 8.74(s, 1H),8.40 (d, J=4.8Hz, 1H), 8.30(dd, J=8.1Hz, 1H), 7.80 (d, J=8.7Hz, 1H), 7.57 (d, J=4.8Hz, 1H), 5.55(s, 2H).
-
- Into a 100-mL round-bottom flask, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carbonitrile (1 g, 3.51 mmol, 1.00 equiv) and sodium hydroxide (1.4 g, 35.00 mmol, 10.00 equiv) in water (30 mL). The resulting solution was stirred for 4 h at 90°C. The pH value of the solution was adjusted to 4-5 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 3x200 mL of ethyl acetate and 3x200 ml of tetrahydrofuran. The combined organic layers were concentrated under vacuum. This resulted in 1 g (94%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid as a yellow solid.
-
- Into a 100-mL round-bottom flask, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid (200 mg, 0.66 mmol, 1.00 equiv) in dichloromethane (30 mL). EDCI (190 mg, 0.99 mmol, 1.50 equiv), 4-dimethylaminopyridine (120 mg, 0.98 mmol, 1.50 equiv), and methanesulfonamide (80 mg, 0.84 mmol, 1.20 equiv) were added to the reaction mixture. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with MeOH:DCM (1:10) as eluent. This resulted in 200 mg (80%) of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)-N-methanesulfonylpyridine-3-carboxamide as a yellow solid.
-
- Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)-N-methanesulfonylpyridine-3-carboxamide (80 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 40°C in an oil bath, and then it was concentrated under vacuum. The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, C18 silica gel; mobile phase, CH3CN/H2O=1/99 increasing to CH3CN/H2O=40/60 within 20 min; Detector, UV 254 nm. This resulted in 20 mg (17%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]-N-methanesulfonylpyridine-3-carboxamide; bis(trifluoroacetic acid) as a white solid. The compound exhibited a melting point of 102-104°C. LC-MS: (ES, m/z):336 [M+1]+ / 354 [M+1+18]+. H-NMR (300MHz, DMSO, ppm): 10.53 (s, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.43 (d, J=4.5Hz, 1H),8.36(dd, J=8.1Hz, 1H), 7.84 (d, J=8.4Hz, 1H), 7.62 (d, J=4.5Hz, 1H), 5.60(s, 2H), 3.37(s, 3H).
- Compounds 207-217 were prepared according to the methods described above.
- 2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 207). 1H NMR (400 MHz, CDCl3)δ 10.32 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 7.97 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 (s, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.11 (s, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.17 (q, J = 8.6 Hz, 2H), 5.10 (s, 2H), 4.39 - 4.32 (m, 2H), 3.70 - 3.63 (m, 2H), 3.37 (s, 3H).
- 2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 208). 1H NMR (400 MHz, CDCl3)δ 10.41 (s, 1H), 8.77 (dd, J = 4.7, 1.6 Hz, 1H), 8.06 (dd, J = 7.9, 1.6 Hz, 1H), 7.97 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.46 (dd, J = 7.9, 4.8 Hz, 1H), 7.13 (s, 1H), 6.46 (d, J = 1.9 Hz, 1H), 5.21 (s, 2H), 4.61 - 4.49 (m, 2H), 3.93 (s, 3H), 2.95 - 2.79 (m, 2H).
- 2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 209). 1H NMR (400 MHz, CDCl3)δ 10.40 (s, 1H), 8.76 (dd, J = 4.7, 1.6 Hz, 1H), 8.06 (dd, J = 7.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H), 7.19 (s, 1H), 6.45 (d, J = 1.9 Hz, 1H), 5.20 (s, 2H), 4.63 - 4.48 (m, 2H), 4.48 - 4.36 (m, 2H), 3.75 (dd, J = 5.4, 3.9 Hz, 2H), 3.45 (s, 3H), 3.01 - 2.69 (m, 2H).
- 2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 210). 1H NMR (400 MHz, CDCl3)δ 10.23 (s, 1H), 8.64 (dd, J = 4.7, 1.6 Hz, 1H), 8.16 (dd, J = 7.9, 1.5 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.19 (q, J = 8.6 Hz, 2H), 5.12 (d, J = 6.1 Hz, 2H), 2.51 (s, 3H).
- 2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 211). 1H NMR (400 MHz, CDCl3)δ 10.31 (s, 1H), 8.75 (dd, J = 4.7, 1.7 Hz, 1H), 8.27 (dd, J = 7.9, 1.6 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 7.9, 4.8 Hz, 1H), 7.33 (d, J= 8.6 Hz, 1H), 7.24 (d, J= 8.6 Hz, 1H), 6.46 (d, J= 1.9 Hz, 1H), 5.18 (s, 2H), 4.61 - 4.44 (m, 2H), 2.96 - 2.75 (m, 2H), 2.62 (s, 3H).
- 3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 212). 1H NMR (400 MHz, CDCl3)δ 10.26 (s, 1H), 8.65 (dd, J = 4.7, 1.5 Hz, 1H), 8.38 (dd, J = 4.4, 1.0 Hz, 1H), 8.19 (dd, J = 7.9, 1.0 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.21 (d, J = 8.6 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 5.19 (q, J = 8.6 Hz, 2H), 5.15 (s, 2H).
- 3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 213). 1H NMR (400 MHz, CDCl3)δ 10.24 (s, 1H), 8.66 (dd, J = 4.7, 1.6 Hz, 1H), 8.39 (dd, J = 4.5, 1.1 Hz, 1H), 8.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.26 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.49 - 4.40 (m, 2H), 2.87 - 2.64 (m, 2H).
- 3-chloro-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 214). 1H NMR (400 MHz, CDCl3)δ 10.51 (s, 1H), 8.77 (dd, J = 4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.23 (s, 2H), 4.66 (sep, J = 6.6 Hz, 1H), 1.49 (d, J = 6.6 Hz, 6H).
- 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde (Compound 215). 1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.69 (dd, J = 4.7, 1.5 Hz, 1H), 8.18 (d, J = 3.7 Hz, 2H), 7.92 (dd, J = 7.9, 1.2 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 7.9, 4.8 Hz, 1H), 7.19 (s, 1H), 6.29 (d, J = 1.8 Hz, 1H), 5.14 (s, 2H), 4.59 (sep, J = 6.6 Hz, 1H), 1.41 (d, J = 6.6 Hz, 6H).
- 3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 216). 1H NMR (400 MHz, CDCl3)δ 10.43 (s, 1H), 8.67 (dd, J = 4.7, 1.5 Hz, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.06 (dd,J = 7.9, 1.3 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 7.9, 4.8 Hz, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.21 - 5.10 (m, 4H).
- 3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (Compound 217). 1H NMR (400 MHz, CDCl3)δ 10.68 (s, 1H), 8.77 (dd, J = 4.7, 1.3 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 7.9, 4.8 Hz, 1H), 6.55 (d, J = 1.9 Hz, 1H), 5.34 - 5.22 (m, 4H), 2.57 (s, 3H).
- Oxygen equilibrium curves (OEC) in purified Hemoglobin S (HbS) were measured by the change in p50, the partial pressure of oxygen at which the heme binding sites in the HbS sample are 50% saturated with oxygen. HbS was purified by a modified procedure (Antonini and Brunori, 1971; Heomoglobin and Myoglobin in their Reactions with Ligands; North Holland Publishing Company; Amsterdam, London) from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. Oxygen equilibrium curves were carried out with a HEMOX analyzer, (TCS Scientific, New Hope, PA). Five hundred µL of 250 µM purified HbS were diluted into 4.5 mL of HEMOX buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH= 7.4) resulting in a final hemoglobin concentration of 25 µM. The compounds were added at the final desired concentrations. The mixture was incubated for 45 min at 37 °C and then transferred to the Hemox sample chamber. The samples were saturated with oxygen by flushing with compressed air for 10 minutes. The samples were then flushed with pure nitrogen and the absorbance of deoxy-Hb was recorded as a function of the solution pO2. The oxygen equilibrium data was then fit to the Hill Model to obtain values for p50. The deoxygenation curves for both HbS alone (control) and HbS in the presence of compound were collected with the TCS software. The p50 for purified Hbs was typically 13.8 + 1.6. Delta p50 values were obtained from the p50 value for control minus the p50 value for HbS treated with compound divided by the p50 value for the control. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.
- The compounds of Table 1 that were where tested in the assay above were all found to have positive delta p50 values. Delta p50% is calculated from [[p50(HbS) - p50(HbS treated with compound)]/p50(HbS)] X 100. Table 2 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and +++ indicates a delta p50% of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 30uM.
Table 2. delta p50% Compound delta p50 1 + 2 ++ (100µM) 3 + 4 + 5 ++ 6 + 7 + 12 + (100µM) 38 + 39 + 40 + (100µM) 41 + 42 + 43 ++ 44 +++ 45 +++ 46 ++ 47 + 48 ++ (100µM) 49 ++ 52 + (100µM) 53 ++ 54 ++ (100µM) 55 + (100µM) 56 + (100µM) 57 ++ (100µM) 58 ++ 59 + 61 + 62 + 63 +++ 64 + 65 ++ 66 ++ 70 + 71 + 74 ++ 75 + 76 + 77 + 78 + 79 ++ 80 ++ 81 + 82 + 83 + 84 ++ 85 + 86 ++ 87 + 88 + 89 + 90 + 91 ++ 92 ++ 93 ++ 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 ++ 104 + 105 + 106 ++ 107 + 108 ++ 109 + 110 + 111 + 113 + 114 + 115 + 116 + 117 + 118 + 119 ++ 120 ++ 121 + 122 + 123 + 124 + 125 + 127 + 128 + 129 ++ 130 ++ 131 ++ 132 +++ 133 ++ 134 ++ 135 + 136 + 137 + 138 + 139 + 140 ++ 142 + 143 ++ 149 +++ 150 +++ 158 ++ 159 +++ 160 +++ 161 ++ 162 +++ 163 +++ 164 ++ 165 ++ 169 ++ 172 ++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 ++ 179 ++ 180 +++ 181 +++ 183 +++ 184 ++ 186 +++ 187 ++ 188 +++ 189 ++ 190 +++ 191 +++ 194 ++ 195 +++ 196 +++ 198 +++ 199 +++ 200 ++ 201 ++ 202 +++ 203 +++ - Polymerization assays are carried out in vitro using purified HBS exchanged into 1.8 M potassium phosphate buffer at pH 7.4. Using a slightly modified protocol (Antonini and Brunori, 1971), HbS is purified by the CRO VIRUSYS, from blood obtained from homozygous sickle cell patients through the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. Compounds are prepared in 100% DMSO and a desired amount is added to 50 µM of purified HBS at a final DMSO concentration of 0.3%. Final potassium phosphate concentration is adjusted to 1.8 M using a combination of 2.5 M potassium phosphate stock solution and water at pH 7.4. The reaction mixture is incubated for an hour at 37 °C and then transferred into a 24-well plate for deoxygenation in a glove box containing 99.5 % nitrogen and 0.5% oxygen. The 24-well plate is not covered and incubated at 4 °C on a plate cooler inside the glove box for one and a half hours. Fifty µL of the reaction mixture is transferred into a 96-well plate and the absorbance at 700 nm is measured every minute for one hour at 37 °C in a plate reader located inside the glove box. A plot of the absorbance against time is fitted using a Boltzman sigmoidal fit and the delay time (from zero to time at half Vmax) is measured. To compare and rank compounds, delay times are expressed as percent delay (%DT), which is defined as the difference in delay times for HBS/compound and HBS alone multiplied by 100 and divided by the delay time for HBS alone.
- Compounds listed below have been tested in the polymerization assay. Activity ranges are defined by the number of dagger (†) symbols indicated. † denotes activity ≥ 40% but ≤ 80%; † † denotes activity > 80% but ≤ 120%; † † † denotes activity > 120% but ≤ 140%; † † † † denotes activity > 160%.
Table 3. % delta Delay Compound % delta Delay 5 † 108 130 † 132 91 149 † 150 ††† 158 † 179 159 †† 160 †† 161 162 †† 173 † 174 †† 195 ††† 198 † 175 †† 162 †† 203 †† 163 †† 181 ††† 206 ††† 178 † 180 † 199 ††† 176 † 177 † 202 ††† 187 †† 164 ††† 165 ††† 169 ††† 186 †††† 188 ††† 189 ††† 190 ††† - A relaxed-to-tense transition assay ("R/T assay") was used to determine the ability of substituted benzaldehyde compounds to mantain the high-oxygen affinity relaxed (R) state of hemoglobin under deoxygenated conditions. This ability can be expressed as a "delta R" value (i.e., the change in the time-period of the R state after hemoglobin is treated with a compound, as compared to the period without treatment with the comound). Delta R is the %R to remaining after the compounds treatment compared with no treatment (e.g. if R% without treatment is 8% while with treatment with a target compound is 48% R at 30 µM, then %R is 40% for that compound.
- A mixture of HbS/A was purified from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. HbS/A (at a final concentration of 3 µM) was incubated for 1 hr at 37°C in presence or absence of compounds in 50 µM potassium phosphate buffer, pH=7.4 and 30 µM 2, 3 diphosphoglycerate (DPG) in 96 well plates in a final volume of 160 µl. Compounds were added at different concentrations (3 µM to 100 µM final concentrations). Plates were covered with a Mylar film. After incubation was completed the Mylar cover was removed and the plates were placed in a Spectrostar Nano plate reader previously heated at 37°C. Five minutes later, N2 (flow rate = 20 L/min) was flowed through the spectrophotometer. Spectroscopic measurements (300 nm to 700 nm) were taken every 5 min for 2 hours. Data analysis was performed by using linear regression from the data retrieved for all wavelengths.
- Table 4 below lists the delta R values where + indicates a delta R of between 0 and 30, ++ indicates a delta R of between 30 and 50, and +++ indicates a delta R of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 30 µM.
Table 4. delta R Compound delta R 5 ++ 43 + (9 µM) 45 ++ (9 µM) 46 + (9 µM) 53 + (9 µM) 58 + (9 µM) 63 ++ (9 µM) 65 + (9 µM) 66 ++ (9 µM) 79 ++ (9 µM) 80 +++ (9 µM) 84 ++ (9 µM) 86 + (9 µM) 91 +++ (9 µM) 92 + (9 µM) 93 + (9 µM) 103 ++ (9 µM) 108 +++ (9 µM) 119 ++ (9 µM) 120 ++ (9 µM) 129 ++ (9 µM) 130 + (9 µM) 131 + (9 µM) 132 ++ 133 ++ (9 µM) 134 + (9 µM) 140 + (9 µM) 143 + (9 µM) 149 + (9 µM) 150 +++ 194 + (9 µM) 158 + (9 µM) 179 + (9 µM) 159 ++ 160 + 161 + (9 µM) 172 + (9 µM) 191 + (9 µM) 173 +++ 195 +++ 174 ++ 196 ++ 198 ++ 175 ++ 162 +++ 203 + (9 µM) 163 ++ 181 + (9 µM) 206 + (9 µM) 178 + (9 µM) 180 ++ 199 + (9 µM) 176 + (9 µM) 177 + (3 µM) 183 ++ 184 ++ 200 + (9 µM) 201 + (9 µM) 202 + (9 µM) 187 +++ (9 µM) 164 ++ (9 µM) 165 + (9 µM) 169 ++ (9 µM) 186 +++ - Oxygen Equilibrium Curves (OEC) of whole blood before and after treatment with different concentrations of substituted benzaldehyde compounds were performed as follows using a HEMOX analyzer (TCS Scientific, New Hope, PA). Blood samples from homozygous sickle cell patients were obtained though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. The hematocrit was adjusted to 20% using autologous plasma and the blood samples were incubated for 1 hour at 37 °C in absence or presence of compounds. 100 µl of these samples were added to 5 mL of Hemox buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH= 7.4) at 37 °C and then transferred to the Hemox sample chamber. The samples were saturated with oxygen by flushing with compressed air for 10 minutes. The samples were then flushed with pure nitrogen and the respective absorbances of oxy- and deoxy-Hb are recorded as a function of the solution pO2. The oxygen equilibrium data were then fitted to the Hill Model to obtain values for p50. The deoxygenation curves for both whole blood alone (control) and whole blood in the presence of the compound were collected with the TCS software.
- Table 5 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and +++ indicates a delta p50% of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 1000 µM. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.
Table 5. delta p50% Values for Whole Blood Assay Compound delta p50% 5 + 44 + 58 + 65 + 74 ++ 79 + 80 + 92 + 93 + 103 + 106 + 108 + 120 + 129 ++ 130 ++ 131 + 132 ++ 133 + 140 + 143 + 149 +++ 150 +++ 194 + 158 + 179 ++ 159 +++ 160 +++ 191 +++ 173 +++ 174 +++ 195 +++ 196 ++ 198 +++ 175 +++ 162 +++ 209 + 163 +++ 181 +++ 206 +++ 178 ++ 180 +++ 199 + 176 +++ 177 +++ 183 +++ 184 +++ 200 +++ 201 + 202 + 187 + 164 ++ 165 + 169 ++ 186 +++ 188 +++ 189 +++ 190 +++ - Any conflict between any reference cited herein and the teaching of this specification is to be resolved in favor of the latter. Similarly, any conflict between an art-recognized definition of a word or phrase and a definition of the word or phrase as provided in this specification is to be resolved in favor of the latter.
Claims (13)
- A compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, for use in a method for treating a condition associated with oxygen deficiencyY is CH2;X is O or CH2;T1, T2, T3, and T4 are C or N, provided that at least one, but no more than one of T1, T2, T3, and T4 is N;Q is selected from the group consisting ofi) heteroaryl optionally substituted with one to three Ra; wherein
R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;ii) aryl substituted with one to three -(CH2)kCO2Rd; wherein
R2 and R5 are independently absent or selected from the group consisting of hydrogen, halo, ORd, O(CH2)zORd O(CH2)zNRdRd , OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R3 and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd O(CH2)zNRdRd , OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;iii) unsubstituted aryl; wherein
R2, R3, and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd O(CH2)zNRdRd , OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R5 is absent or is ORd; andiv) heterocycloalkyl optionally substituted with one to three Ra; wherein
R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd O(CH2)zNRdRd , OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;each Ra is independently selected from the group consisting of halo, Rb, ORd, O(CH2)uORd, O(CH2)uNRdRd, O(CH2)uNRdC(O)Re, O(CH2)uNRdC(O)2Re, O(CH2)uNRdS(O)2Re, NH2, -(CH2)kOC(O)Re, -(CH2)kSRd, CN, NO2, -(CH2)kCO2(C1-8alkyl)OH, -(CH2)kCO2(C1-8alkyl)(heteroaryl)C(O)(C1-8alkyl), -(CH2)kCO2Rd, -(CH2)kCONRdRd, -(CH2)kNRdC(O)Re, -(CH2)kNRdC(O)2Re, -(CH2)kC(O)Rd, -(CH2)kOC(O)NRdRd, -NRd(CH2)uORd, -NRd(CH2)uNRdRd, -NRd(CH2)uNRdC(O)Re, -NRd(CH2)uNRdC(O)2Re, -NRd(CH2)uNRdS(O)2Re, -(CH2)kNRdC(O)2Rd, -(CH2)kNRdC(O)NRdRd, -(CH2)kS(O)Re, -(CH2)kS(O)2Re, -(CH2)kNRdS(O)2Re, -C(O)(CH2)kNRdS(O)2Re, -(CH2)kC(O)NRdS(O)2Re, -(CH2)kS(O)2NRdRd, N3, -(CH2)karyl optionally substituted with one to three Rc, -NRd(CH2)karyl optionally substituted with one to three Rc, -(CH2)kheteroaryl optionally substituted with one to three Rc, -NRd(CH2)kheteroaryl optionally substituted with one to three Rc, -(CH2)kheterocycloalkyl optionally substituted with one to three Rc, and -NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;each Rb is independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and C2-8alkynyl, each optionally independently substituted with one to three halo, ORd, or NRdRd;each Rc is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, haloC2-8alkynyl, (CH2)mORf, OC(O)Rg, SRf, CN, NO2, (CH2)mCO2Rf, CONRfRf, C(O)Rf, OC(O)NRfRf, (CH2)mNRfRf, NRfC(O)Rg, NRC(O)2Rg, NRfC(O)NRfRf, S(O)Rg, S(O)2Rg, NRfS(O)2Rg, S(O)2NRfRf, N3, (Rf)mSiC1-8alkyl, heteroaryl optionally substituted with one to three Rh, cycloalkyl optionally substituted with one to three Rh, and heterocycloalkyl optionally substituted with one to three Rh where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;each Rh is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, ORj, OC(O)R, SRj, NO2, CO2Rj, CONRjRj, C(O)Rj, OC(O)NRjRj, NRjRj, NRjC(O)Rt, NRjC(O)2Rt, NRjC(O)NRjRj, S(O)Rt, S(O)2Rt, NRjS(O)2Rt, and S(O)2NRjRj;Rd, Rf, and Rj are each independently selected from the group consisting of hydrogen, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, and haloC2-8alkynyl; andRe, Rg, and Rt are each independently selected from the group consisting of C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, and haloC2-8alkynyl;wherein the condition is selected from the group consisting of sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound. - The compound or tautomer or pharmaceutically acceptable salt for use according to claim 1, wherein R2 and R3 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, CO2Rd, CONRdRd, and C(O)Rd, where z is 1, 2, or 3.
- The compound or tautomer or pharmaceutically acceptable salt for use according to claim 1, whereina) T2 is N; R2 and R5 are H; R3 is absent; and R4 is selected from C1-8alkoxy, haloC1-8alkoxy, and O(CH2)2OC1-8alkyl;b) T2 is N; R2 and R4 are H; R3 is absent; and R5 is selected from hydroxy and C1-8alkoxy; orc) T4 is N; R2 and R3 are H; R5 is absent; and R4 is selected from C1-8alkyl and C1-8alkoxy.
- The compound or tautomer or pharmaceutically acceptable salt for use according to claim 3, wherein:(a) Q is selected from the group consisting of an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and wherein Q is optionally substituted with one to three Ra; or
- The compound or tautomer or pharmaceutically acceptable salt for use according to claim 1, wherein:T1 is N; R3, R4, and R5 are H; and R2 is absent;T2 is N; R2, R4, and R5 are H; and R3 is absent;T3 is N; R2, R3, and R5 are H; and R4 is absent; orT4 is N; R2, R3, and R4 are H; and R5 is absent.
- The compound or tautomer or pharmaceutically acceptable salt for use according to claim 5, wherein:(a) Q is selected from the group consisting of an imidazopyridinyl group, a pyrrolopyridinyl group, a pyrazolopyridinyl group, a triazolopyridinyl group, a pyrazolopyrazinyl group, a pyridinyl group, a pyrazinyl group, an oxazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyrazolyl group, a quinolinyl group, an isoquinolinyl group, an indazolyl group, a benzooxazolyl group, a naphthyridinyl group, and a quinoxalinyl group; and Q is optionally substituted with one to three Ra; or
- The compound for use according to claim 1, selected from:4-(pyridin-3-ylmethoxy)nicotinaldehyde,3-(pyridin-3-ylmethoxy)isonicotinaldehyde,2-(imidazo[1,2-a]pyridin-8-ylmethoxy)nicotinaldehyde,3-(imidazo[1,2-a]pyridin-8-ylmethoxy)picolinaldehyde,5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,3-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde,3-(imidazo[1,5-a]pyridin-8-ylmethoxy)isonicotinaldehyde,2-methoxy-5-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)isonicotinaldehyde,8-((3-formylpyridin-2-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide,8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide,5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde,2-(2-(imidazo[1,2-a]pyridin-8-yl)ethyl)nicotinaldehyde,5-(2-(imidazo[1,2-a]pyridin-8-yl)ethyl)-2-methoxyisonicotinaldehyde,5-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyrazolo[1,5-a]pyrazine-2-carboxamide,5-((2-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(imidazo[1,2-a]pyridin-2-ylmethoxy)nicotinaldehyde,2-methoxy-5-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methoxy)isonicotinaldehyde,2-(imidazo[1,2-a]pyridin-8-ylmethoxy)nicotinaldehyde,5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methylisonicotinaldehyde,3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methoxy)isonicotinaldehyde,3-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde,3-(pyrrolo[1,2-a]pyrazin-6-ylmethoxy)isonicotinaldehyde,6-((4-formylpyridin-3-yloxy)methyl)pyrrolo[1,2-a]pyrazine-7-carbonitrile,6-((4-formylpyridin-3-yloxy)methyl)pyrrolo[1,2-a]pyrazine-7-carboxamide,3-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)isonicotinaldehyde,3-(pyrazolo[1,5-a]pyrazin-3-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((6-oxo-1,6-dihydropyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)isonicotinaldehyde,2-methoxy-5-(oxazol-5-ylmethoxy)isonicotinaldehyde,5-((1H-imidazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-imidazol-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((4H-1,2,4-triazol-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-tetrazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-pyrazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-pyrazol-4-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-(oxazol-4-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((2-methylpyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((4-methylpyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((6-methylpyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-(pyridin-3-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde,5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehyde,2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((3-methylpyridin-4-yl)methoxy)isonicotinaldehyde,5-((3-bromopyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde,2-methoxy-5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methoxy)isonicotinaldehyde,methyl 2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate,2-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)isonicotinaldehyde,5-((3-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((8-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde,5-((3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)isonicotinaldehyde,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile,5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile,5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((5-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((5-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((4-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((5-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid,2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde,6-methyl-3-(quinolin-3-ylmethoxy)picolinaldehyde,5-(isoquinolin-7-ylmethoxy)-2-methoxyisonicotinaldehyde,3-(isoquinolin-7-ylmethoxy)-6-methylpicolinaldehyde,2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde,6-methyl-3-((1-methyl-1H-indazol-4-yl)methoxy)picolmaldehyde,tert-butyl 4-((2-formyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate,5-((1H-indazol-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((1H-indazol-4-yl)methoxy)-6-methylpicolmaldehyde,6-methoxy-3-((1-methyl-1H-indazol-6-yl)methoxy)picolmaldehyde,2-methoxy-5-((1-methyl-1H-indazol-7-yl)methoxy)isonicotinaldehyde,6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolmaldehyde,6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde,3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde,6-methyl-3-(quinolin-2-ylmethoxy)picolinaldehyde,5-((4-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-bromoimidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carbonitrile,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinonitrile,3-(benzo[d]oxazol-4-ylmethoxy)-6-methylpicolinaldehyde,8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinamide,5-((6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde,5-((6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1,5-naphthyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde,5-((1H-indazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolmaldehyde,3-((3-chloro-1-methyl-1H-indazol-5-yl)methoxy)-6-methylpicolmaldehyde,2-methoxy-5-((1-methyl-1H-indazol-5-yl)methoxy)isonicotinaldehyde,5-((3-chloro-1-methyl-1H-indazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-6-methylpicolinaldehyde,5-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinamide,5-((2-chloroquinolin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1H-pyrazol-5-yl)quinolm-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-(quinoxalin-2-ylmethoxy)isonicotinaldehyde,6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde,2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde,6-methyl-3-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methoxy)picolinaldehyde,2-methoxy-5-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methoxy)isonicotinaldehyde,5-((7-(1H-pyrazol-3-yl)imidazo[1,5-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((5-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde,6-methyl-3-(pyridin-3-ylmethoxy)picolinaldehyde,methyl 8-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate,methyl 2-bromo-8-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate,3-(imidazo[1,5-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde,5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,3-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(4-(1H-pyrazol-3-yl)piperazin-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehyde,5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,5-([2,3'-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2'-methoxy-[2,3'-bipyridin]-3-yl)methoxy)isonicotinaldehyde,methyl 4-(((2-formylpyridin-3-yl)oxy)methyl)benzoate,4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid,4-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid,methyl 3-(((4-formylpyridin-3-yl)oxy)methyl)benzoate,methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate,3-(((4-formylpyridin-3-yl)oxy)methyl)benzoic acid,3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid,3-(((2-formylpyridin-3-yl)oxy)methyl)benzoic acid,2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)picolinaldehyde,3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde,2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde,5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde,5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate,5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-(benzyloxy)-5-hydroxyisonicotinaldehyde,3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde,5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid,2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)picolinic acid (1:1),5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde,5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-cyclohexyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid,methyl 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate,3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid,3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid,3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid,6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinonitrile 2,2,2-trifluoroacetate,6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid,6-(((4-formylpyridin-3-yl)oxy)methyl)nicotinic acid hydrochloride,6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide,2,2,2-trifluoroacetic acid : 6-(((4-formylpyridin-3-yl)oxy)methyl)-N-(methylsulfonyl)nicotinamide (2:1),2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methyl-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-chloro-5-((2-(I-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methylisonicotinaldehyde,3-chloro-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, and3-methyl-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,or a tautomer or pharmaceutically acceptable salt thereof.
- A compound of formula (I'), or a tautomer or pharmaceutically acceptable salt thereof,Y is CH2;X is O or CH2;T1, T2, T3, and T4 are C or N, provided that at least one, but no more than one of T1, T2, T3, and T4 is N;Q is selected from the group consisting ofi) heteroaryl optionally substituted with one to three Ra; wherein
R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;ii) aryl substituted with one to three -(CH2)kCO2Rd; wherein
R2 and R5 are independently absent or selected from the group consisting of hydrogen, halo, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R3 and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;iii) unsubstituted aryl; wherein
R2, R3, and R4 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3; and
R5 is absent or is ORd; andiv) heterocycloalkyl optionally substituted with one to three Ra; wherein
R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, Rb, ORd, O(CH2)zORd, O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3 where z is 1, 2, or 3;each Ra is independently selected from the group consisting of halo, Rb, ORd, O(CH2)uORd, O(CH2)uNRdRd, O(CH2)uNRdC(O)Re, O(CH2)uNRdC(O)2Re, O(CH2)uNRdS(O)2Re, NH2, -(CH2)kOC(O)Re, -(CH2)kSRd, CN, NO2, -(CH2)kCO2(C1-8alkyl)OH, -(CH2)kCO2(C1-8alkyl)(heteroaryl)C(O)(C1-8alkyl), -(CH2)kCO2Rd, -(CH2)kCONRdRd, -(CH2)kNRdC(O)Re, -(CH2)kNRdC(O)2Re, -(CH2)kC(O)Rd, -(CH2)kOC(O)NRdRd, -NRd(CH2)uORd, -NRd(CH2)uNRdRd, -NRd(CH2)uNRdC(O)Re, -NRd(CH2)uNRdC(O)2Re, -NRd(CH2)uNRdS(O)2Re, -(CH2)kNRdC(O)2Rd, -(CH2)kNRdC(O)NRdRd, -(CH2)kS(O)Re, -(CH2)kS(O)2Re, -(CH2)kNRdS(O)2Re, -C(O)(CH2)kNRdS(O)2Re, -(CH2)kC(O)NRdS(O)2Re, -(CH2)kS(O)2NRdRd, N3, -(CH2)karyl optionally substituted with one to three Rc, -NRd(CH2)karyl optionally substituted with one to three Rc, -(CH2)kheteroaryl optionally substituted with one to three Rc, -NRd(CH2)kheteroaryl optionally substituted with one to three Rc, -(CH2)kheterocycloalkyl optionally substituted with one to three Rc, and -NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6;each Rb is independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and C2-8alkynyl, each optionally independently substituted with one to three halo, ORd, or NRdRd;each Rc is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, haloC2-8alkynyl, (CH2)mORf, OC(O)Rg, SRf, CN, NO2, (CH2)mCO2Rf, CONRfRf, C(O)Rf, OC(O)NRfRf, (CH2)mNRfRf, NRfC(O)Rg, NRC(O)2Rg, NRfC(O)NRfRf, S(O)Rg, S(O)2Rg, NRfS(O)2Rg, S(O)2NRfRf, N3, (Rf)mSiC1-8alkyl, heteroaryl optionally substituted with one to three Rh, cycloalkyl optionally substituted with one to three Rh, and heterocycloalkyl optionally substituted with one to three Rh where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;each Rh is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, ORj, OC(O)R, SRj, NO2, CO2Rj, CONRjRj, C(O)Rj, OC(O)NRjRj, NRjRj, NRjC(O)Rt, NRjC(O)2Rt, NRjC(O)NRjRj, S(O)Rt, S(O)2Rt, NRjS(O)2Rt, and S(O)2NRjRj;Rd, Rf, and Rj are each independently selected from the group consisting of hydrogen, C1-8 alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl; andRe, Rg, and Rt are each independently selected from the group consisting of C1-8alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl;and wherein furthera) T2 is N; R2 and R5 are H; R3 is absent; and R4 is selected from C1-8alkoxy, haloC1-8alkoxy, and O(CH2)2OC1-8alkyl;b) T2 is N; R2 and R4 are H; R3 is absent; and R5 is selected from hydroxy and C1-8alkoxy; orc) T4 is N; R2 and R3 are H; R5 is absent; and R4 is selected from C1-8alkyl and C1-8alkoxy. - The compound, tautomer or pharmaceutically acceptable salt according to claim 8, wherein Y, X, T1 to T4, R2 to R5 and Q are as defined in any one of claims 4 to 6.
- The compound according to claim 8, selected from the group consisting of:5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide,5-(2-(imidazo[1,2-a]pyridin-8-yl)ethyl)-2-methoxyisonicotinaldehyde,5-((1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyrazolo[1,5-a]pyrazine-2-carboxamide,5-((2-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((6-oxo-1,6-dihydropyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-oxo-1,2-dihydropyridin-4-yl)methoxy)isonicotinaldehyde,2-methoxy-5-(oxazol-5-ylmethoxy)isonicotinaldehyde,5-((1H-imidazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-imidazol-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((4H-1,2,4-triazol-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-tetrazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-pyrazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1H-pyrazol-4-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-(oxazol-4-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((2-methylpyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((4-methylpyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((6-methylpyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-(pyridin-3-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((5-methylpyridin-3-yl)methoxy)isonicotinaldehyde,5-(isoquinolin-1-ylmethoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-(quinolin-2-ylmethoxy)isonicotinaldehyde,2-methoxy-5-(pyridin-4-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((3-methylpyridin-4-yl)methoxy)isonicotinaldehyde,5-((3-bromopyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-(imidazo[1,2-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde,2-methoxy-5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methoxy)isonicotinaldehyde,methyl 2-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-8-carboxylate,2-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)isonicotinaldehyde,5-((3-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((8-bromoimidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methoxy)isonicotinaldehyde,5-((3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((8-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)isonicotinaldehyde,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile,5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile,5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((5-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((5-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((4-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((5-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinic acid,2-methoxy-5-(quinolin-3-ylmethoxy)isonicotinaldehyde,6-methyl-3-(quinolin-3-ylmethoxy)picolinaldehyde,5-(isoquinolin-7-ylmethoxy)-2-methoxyisonicotinaldehyde,3-(isoquinolin-7-ylmethoxy)-6-methylpicolinaldehyde,2-methoxy-5-((1-methyl-1H-indazol-4-yl)methoxy)isonicotinaldehyde,6-methyl-3-((1-methyl-1H-indazol-4-yl)methoxy)picolmaldehyde,tert-butyl 4-((2-fonnyl-6-methylpyridin-3-yloxy)methyl)-1H-indazole-1-carboxylate,5-((1H-indazol-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((1H-indazol-4-yl)methoxy)-6-methylpicolinaldehyde,6-methoxy-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde,2-methoxy-5-((1-methyl-1H-indazol-7-yl)methoxy)isonicotinaldehyde,6-methyl-3-((1-methyl-1H-indazol-6-yl)methoxy)picolinaldehyde,6-methyl-3-((1-methyl-1H-indazol-7-yl)methoxy)picolinaldehyde,3-(isoquinolin-1-ylmethoxy)-6-methylpicolinaldehyde,6-methyl-3-(quinolin-2-ylmethoxy)picolinaldehyde,5-((4-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-bromoimidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carbonitrile,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinonitrile,3-(benzo[d]oxazol-4-ylmethoxy)-6-methylpicolinaldehyde,8-((4-formyl-6-methoxypyridin-3-yloxy)methyl)imidazo[1,2-a]pyridine-6-carboxamide,5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinamide,5-((6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,5-(benzo[d]oxazol-4-ylmethoxy)-2-methoxyisonicotinaldehyde,5-((6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((1,5-naphthyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((1,5-naphthyridin-4-yl)methoxy)-6-methylpicolinaldehyde,5-((1H-indazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,6-methyl-3-((1-methyl-1H-indazol-5-yl)methoxy)picolmaldehyde,3-((3-chloro-1-methyl-1H-indazol-5-yl)methoxy)-6-methylpicolmaldehyde,2-methoxy-5-((1-methyl-1H-indazol-5-yl)methoxy)isonicotinaldehyde,5-((3-chloro-1-methyl-1H-indazol-5-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-6-methylpicolinaldehyde,5-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinamide,5-((2-chloroquinolin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1H-pyrazol-5-yl)quinolin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-(quinoxalin-2-ylmethoxy)isonicotinaldehyde,6-methyl-3-(quinolin-5-ylmethoxy)picolinaldehyde,2-methoxy-5-(quinolin-5-ylmethoxy)isonicotinaldehyde,6-methyl-3-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methoxy)picolinaldehyde,2-methoxy-5-((1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methoxy)isonicotinaldehyde,5-((7-(1H-pyrazol-3-yl)imidazo[1,5-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((5-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((6-(2H-tetrazol-5-yl)imidazo[1,2-a]pyridin-8-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((3-(1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((2-(1H-pyrazol-1-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde,6-methyl-3-(pyridin-3-ylmethoxy)picolinaldehyde,methyl 8-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate,methyl 2-bromo-8-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)imidazo[1,2-a]pyridine-6-carboxylate,3-(imidazo[1,5-a]pyridin-8-ylmethoxy)-6-methylpicolinaldehyde,5-(imidazo[1,5-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1,3-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-ethyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(4-(1H-pyrazol-3-yl)piperazin-1-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-8-ylmethoxy)isonicotinaldehyde,2-methoxy-5-((2-phenylpyridin-3-yl)methoxy)isonicotinaldehyde,5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methoxy)-2-methoxyisonicotinaldehyde,5-([2,3'-bipyridin]-3-ylmethoxy)-2-methoxyisonicotinaldehyde,2-methoxy-5-((2-(o-tolyl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2'-methoxy-[2,3'-bipyridin]-3-yl)methoxy)isonicotinaldehyde,4-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid,methyl 3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoate,3-(((2-formyl-6-methylpyridin-3-yl)oxy)methyl)benzoic acid,2-methoxy-5-((2-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-propyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-((2-(1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-methylpicolinaldehyde,2-(difluoromethoxy)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-(2-methoxyethoxy)isonicotinaldehyde,5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-(2-methoxyethoxy)isonicotinaldehyde,5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde,3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinate,5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,3-(benzyloxy)-5-hydroxyisonicotinaldehyde,3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde,5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-cyclobutyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-cyclohexyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,5-((2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde,2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetic acid,methyl 3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate,3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid,3-(5-(3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid,3-(((4-formyl-6-methoxypyridin-3-yl)oxy)methyl)benzoic acid,2-(2-methoxyethoxy)-5-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,2-methoxy-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde, and2-(2-methoxyethoxy)-5-((2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde,or a tautomer or pharmaceutically acceptable salt thereof.
- A pharmaceutical composition comprising a compound of any of claims 8 to 10, or a tautomer or pharmaceutically acceptable salt thereof.
- The compound, tautomer or pharmaceutically acceptable salt for use according to any one of claims 1 to 7, wherein the condition is sickle cell disease.
- The compound, tautomer or pharmaceutically acceptable salt for use according to any one of claims 1 to 7, wherein the condition is a pulmonary disorder.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161581063P | 2011-12-28 | 2011-12-28 | |
US201261661327P | 2012-06-18 | 2012-06-18 | |
PCT/US2012/072183 WO2013102145A1 (en) | 2011-12-28 | 2012-12-28 | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2797597A1 EP2797597A1 (en) | 2014-11-05 |
EP2797597A4 EP2797597A4 (en) | 2015-06-24 |
EP2797597B1 true EP2797597B1 (en) | 2020-02-26 |
Family
ID=48698670
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP12862096.0A Active EP2797597B1 (en) | 2011-12-28 | 2012-12-28 | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
Country Status (5)
Country | Link |
---|---|
US (5) | US9012450B2 (en) |
EP (1) | EP2797597B1 (en) |
ES (1) | ES2790358T3 (en) |
HK (1) | HK1203412A1 (en) |
WO (1) | WO2013102145A1 (en) |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AP2014007805A0 (en) | 2011-12-28 | 2014-07-31 | Cytokinetics Inc The Regents Of The University Of California | Substituted benzaldehyde compounds and methods fortheir use in increasing tissue oxygenation |
US9012450B2 (en) | 2011-12-28 | 2015-04-21 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
MX2015011769A (en) | 2013-03-15 | 2016-06-02 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin. |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
EP2970308B1 (en) | 2013-03-15 | 2021-07-14 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
SG10201802911RA (en) | 2013-03-15 | 2018-05-30 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin |
WO2015031285A1 (en) * | 2013-08-27 | 2015-03-05 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
EA201992707A1 (en) | 2013-11-18 | 2020-06-30 | Глобал Блад Терапьютикс, Инк. | COMPOUNDS AND THEIR APPLICATIONS FOR HEMOGLOBIN MODULATION |
US9248199B2 (en) | 2014-01-29 | 2016-02-02 | Global Blood Therapeutics, Inc. | 1:1 adducts of sickle hemoglobin |
WO2015116061A1 (en) * | 2014-01-29 | 2015-08-06 | Global Blood Therapeutics, Inc. | 1:1 adducts of sickle hemoglobin |
PT3102208T (en) | 2014-02-07 | 2021-04-05 | Global Blood Therapeutics Inc | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
WO2016043849A2 (en) | 2014-07-24 | 2016-03-24 | Global Blood Therapeutics, Inc. | Compounds for treating acute respiratory distress syndrome or a negative effect thereof |
TWI713497B (en) * | 2015-02-26 | 2020-12-21 | 南韓商愛思開生物製藥股份有限公司 | Imidazopyrimidine and imidazotriazine derivative, and pharmaceutical composition comprising the same |
MA41841A (en) | 2015-03-30 | 2018-02-06 | Global Blood Therapeutics Inc | ALDEHYDE COMPOUNDS FOR THE TREATMENT OF PULMONARY FIBROSIS, HYPOXIA, AND AUTOIMMUNE AND CONNECTIVE TISSUE DISEASES |
BR112018011272A2 (en) | 2015-12-04 | 2018-11-21 | Global Blood Therapeutics Inc | 2-hydroxy-6 - ((2- (1-isopropyl-1h-pyrazol-5-yl) pyridin-3-yl) methoxy) benzaldehyde dosage regimens |
TWI752307B (en) | 2016-05-12 | 2022-01-11 | 美商全球血液治療公司 | Novel compound and method of preparing compound |
CN105884682B (en) * | 2016-05-24 | 2018-10-19 | 合肥工业大学 | A kind of synthetic method of 2,6- pyridinedicarboxylic acids methyl esters crystal |
US10787430B2 (en) | 2016-06-17 | 2020-09-29 | Fronthera U.S. Pharmaceuticals Llc | Hemoglobin modifier compounds and uses thereof |
TWI778983B (en) | 2016-10-12 | 2022-10-01 | 美商全球血液治療公司 | Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
DK3483164T3 (en) | 2017-03-20 | 2020-03-23 | Forma Therapeutics Inc | PYRROLOPYRROL COMPOSITIONS AS PYRUVAT KINASE (PKR) ACTIVATORS |
US10364245B2 (en) | 2017-06-07 | 2019-07-30 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
UY37764A (en) | 2017-06-13 | 2019-01-02 | Glaxosmithkline Ip Dev Ltd | NEW INHIBITING COMPOUNDS OF PROSTAGLANDINA D SINTASA HEMATOPOYÉTICA (H-PGDS) |
US20230055923A1 (en) | 2018-09-19 | 2023-02-23 | Forma Therapeutics, Inc. | Activating pyruvate kinase r |
US20220031671A1 (en) | 2018-09-19 | 2022-02-03 | Forma Therapeutics, Inc. | Treating sickle cell disease with a pyruvate kinase r activating compound |
EP3860975B1 (en) | 2018-10-01 | 2023-10-18 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin for the treatment of sickle cell disease |
MX2021005887A (en) | 2018-11-19 | 2021-09-14 | Global Blood Therapeutics Inc | 2-formyl-3-hydroxyphenyloxymethyl compounds capable of modulating hemoglobin. |
US11014908B2 (en) * | 2018-11-29 | 2021-05-25 | Pfizer Inc. | Chemical compounds |
BR112022000325A2 (en) | 2019-07-11 | 2022-03-15 | Escape Bio Inc | Indazoles and azaindazoles as lrrk2 inhibitors |
Family Cites Families (257)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE258226C (en) | ||||
DE276479C (en) | ||||
DE226590C (en) | ||||
NL293714A (en) | 1956-02-13 | 1900-01-01 | ||
BE787580A (en) | 1971-08-13 | 1973-02-14 | Hoechst Ag | FURANNE DERIVATIVE PREPARATION PROCESS |
BE787576A (en) | 1971-08-13 | 1973-02-14 | Hoechst Ag | BENZOFURANE DERIVATIVES AND THEIR USE AS OPTICAL BLASTERS |
GB1409865A (en) | 1973-02-13 | 1975-10-15 | Science Union & Cie | Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them |
GB1593417A (en) | 1976-12-22 | 1981-07-15 | Squibb & Sons Inc | Carbocyclic-fused pyrazolopyridine derivatives |
US4062858A (en) | 1976-12-22 | 1977-12-13 | E. R. Squibb & Sons, Inc. | Derivatives of 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-ones and 11(1H)-imines |
EP0010063B1 (en) | 1978-10-04 | 1982-12-29 | Ciba-Geigy Ag | Process for the preparation of furanyl-benzazoles |
DE2853765A1 (en) | 1978-12-13 | 1980-06-26 | Bayer Ag | METHOD FOR PRODUCING BENZIMIDAZOLYLBENZOFURANES |
DE2904829A1 (en) | 1979-02-08 | 1980-08-14 | Bayer Ag | METHOD FOR PRODUCING BENZIMIDAZOLYLBENZOFURANE |
JPS5649335A (en) | 1979-06-29 | 1981-05-02 | Wellcome Found | Ether compound |
IT1193786B (en) | 1980-12-18 | 1988-08-24 | Wellcome Found | ETHEREAL COMPOUNDS EQUIPPED WITH MITIGATING ACTIVITY OF INTERMEDIATE HEMOGLOBINOPATHIES AND PROCEDURE FOR THEIR PREPARATION |
JPS5929667A (en) | 1982-08-13 | 1984-02-16 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
US4478834A (en) | 1983-02-11 | 1984-10-23 | Usv Pharmaceutical Corporation | Dihydropyridines and their use in the treatment of asthma |
GB8402740D0 (en) | 1984-02-02 | 1984-03-07 | Scras | Furo-(3 4-c)-pyridine derivatives |
JPS6140236A (en) | 1984-08-02 | 1986-02-26 | Yamanouchi Pharmaceut Co Ltd | Hydroquinone derivative |
DE3431004A1 (en) | 1984-08-23 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | NEW 3-PYRIDYL COMPOUNDS AND METHOD FOR THEIR PRODUCTION |
GB8603475D0 (en) | 1986-02-12 | 1986-03-19 | Glaxo Group Ltd | Chemical compounds |
DK111387A (en) | 1986-03-05 | 1987-09-06 | Otsuka Pharma Co Ltd | CARBOSTYRIL DERIVATIVES AND SALTS THEREOF, MEDICINE CONTAINING SUCH DERIVATIVES AND PROCEDURES FOR THE PREPARATION OF THE DERIVATIVES |
US4831041A (en) | 1986-11-26 | 1989-05-16 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridine compounds and processes for preparation thereof |
EP0278686A1 (en) | 1987-02-07 | 1988-08-17 | The Wellcome Foundation Limited | Pyridopyrimidines methods for their preparation and pharmaceutical formulations thereof |
DD258226A1 (en) | 1987-03-05 | 1988-07-13 | Fahlberg List Veb | PROCESS FOR PRODUCING AROXYMETHYLCHINOXALINES |
JPH07121937B2 (en) | 1987-03-18 | 1995-12-25 | 大塚製薬株式会社 | Carbostyril derivative |
JPS63258463A (en) | 1987-04-14 | 1988-10-25 | Kumiai Chem Ind Co Ltd | 2-phenoxypyrimidine derivative and herbicide |
GB8711802D0 (en) | 1987-05-19 | 1987-06-24 | Fujisawa Pharmaceutical Co | Dithioacetal compounds |
GB8718940D0 (en) | 1987-08-11 | 1987-09-16 | Glaxo Group Ltd | Chemical compounds |
US4920131A (en) | 1987-11-03 | 1990-04-24 | Rorer Pharmaceutical Corp. | Quinoline derivatives and use thereof as antagonists of leukotriene D4 |
JP2650038B2 (en) | 1988-01-27 | 1997-09-03 | サントリー株式会社 | Pyrrolitidine compounds and uses thereof |
JPH01305081A (en) | 1988-04-04 | 1989-12-08 | E R Squibb & Sons Inc | 3-acylamino-1-((((substituted sulfonyl)amino) carbonyl)amino)-2-azetinones |
US4952574A (en) | 1988-09-26 | 1990-08-28 | Riker Laboratories, Inc. | Antiarrhythmic substituted N-(2-piperidylmethyl)benzamides |
IE81170B1 (en) | 1988-10-21 | 2000-05-31 | Zeneca Ltd | Pyridine derivatives |
DD276480A1 (en) | 1988-10-26 | 1990-02-28 | Fahlberg List Veb | PROCESS FOR THE PREPARATION OF NAPHTHO / 2,1-B / FUR-2-YLCHINOXALINES |
DD276479A1 (en) | 1988-10-26 | 1990-02-28 | Fahlberg List Veb | PROCESS FOR THE PREPARATION OF BENZO / B / FUR-2-YLCHINOXALINES |
US5236917A (en) | 1989-05-04 | 1993-08-17 | Sterling Winthrop Inc. | Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
IT1230859B (en) | 1989-06-05 | 1991-11-08 | Corvi Camillo Spa | 2 ALCHYLYLPHENOLS SUBSTITUTED FOR ANTI-INFLAMMATORY ACTION, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
EP0453210A3 (en) | 1990-04-19 | 1993-01-13 | Imperial Chemical Industries Plc | Pyridine derivatives |
NZ238576A (en) | 1990-06-18 | 1994-12-22 | Merck & Co Inc | Pyridinone derivatives, preparation and pharmaceutical compositions thereof |
AU653734B2 (en) | 1990-06-19 | 1994-10-13 | Meiji Seika Kabushiki Kaisha | Substituted 4-biphenylmethoxypyridine derivatives |
NL9001752A (en) | 1990-08-02 | 1992-03-02 | Cedona Pharm Bv | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES. |
IL99731A0 (en) | 1990-10-18 | 1992-08-18 | Merck & Co Inc | Hydroxylated pyridine derivatives,their preparation and pharmaceutical compositions containing them |
US5403816A (en) | 1990-10-25 | 1995-04-04 | Kumiai Chemical Industry Co., Ltd. | Picolinic acid derivative and herbicidal composition |
JPH05301872A (en) | 1992-04-23 | 1993-11-16 | Kumiai Chem Ind Co Ltd | Picolinic acid derivativee and herbicide |
AU1183992A (en) | 1991-02-08 | 1992-09-07 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Complexing agents |
JPH0641118A (en) | 1991-05-31 | 1994-02-15 | Kumiai Chem Ind Co Ltd | Picolinic acid derivative and herbicide |
US5185251A (en) | 1991-06-07 | 1993-02-09 | Merck & Co., Inc. | Microbial transformation of a substituted pyridinone using actinoplanacete sp. MA 6559 |
JP2600644B2 (en) | 1991-08-16 | 1997-04-16 | 藤沢薬品工業株式会社 | Thiazolyl benzofuran derivative |
FR2680512B1 (en) | 1991-08-20 | 1995-01-20 | Adir | NOVEL 2,4-THIAZOLIDINEDIONE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
US5202243A (en) | 1991-10-04 | 1993-04-13 | Merck & Co., Inc. | Method of hydroxylating 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2-(1H)-pyridinone by incubation with liver slices |
GB9203798D0 (en) | 1992-02-21 | 1992-04-08 | Fujisawa Pharmaceutical Co | Quinolylbenzofuran derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
JPH07508527A (en) | 1992-07-01 | 1995-09-21 | ビイク グルデン ロンベルク ヒェーミッシェ ファブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | complexing agent |
US5290941A (en) | 1992-10-14 | 1994-03-01 | Merck & Co., Inc. | Facile condensation of methylbenzoxazoles with aromatic aldehydes |
WO1994022857A1 (en) | 1993-04-07 | 1994-10-13 | Taiho Pharmaceutical Co., Ltd. | Thiazolidine derivative and pharmaceutical composition containing the same |
DE4318550A1 (en) | 1993-06-04 | 1994-12-08 | Boehringer Mannheim Gmbh | Arylidene-4-oxo-2-thioxo-3-thiazolidinecarboxylic acids, process for their preparation and pharmaceutical compositions containing them |
IL110151A (en) | 1993-06-30 | 1998-10-30 | Sankyo Co | Amide derivatives and pharmaceutical compositions containing them |
JPH0725882A (en) | 1993-07-07 | 1995-01-27 | Res Dev Corp Of Japan | Intermediate for production of acromelic acid b and e and its production |
EP0637586B1 (en) | 1993-08-05 | 1999-06-02 | HOECHST MARION ROUSSEL, Inc. | 2-(Piperidin-4-yl, pyridin-4-yl and tetrahydropyridin-4-yl)-benzofuran-7-carbamate derivatives, their preparation and their use as acetylcholinesterase inhibitors |
EP0640609A1 (en) | 1993-08-24 | 1995-03-01 | Ono Pharmaceutical Co., Ltd. | Fused phenol derivatives having inhibitory activity on TXA2 synthetase, and 5-lipoxygenase and scavenging activity on oxygen species |
US5840900A (en) | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5880131A (en) | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5965566A (en) | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5605976A (en) | 1995-05-15 | 1997-02-25 | Enzon, Inc. | Method of preparing polyalkylene oxide carboxylic acids |
AU7992594A (en) | 1993-11-19 | 1995-06-06 | Ciba-Geigy Ag | Benzothiophene derivatives possessing a methoxyimino substituent as microbicides |
EP0658559A1 (en) | 1993-12-14 | 1995-06-21 | Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. | Thienothiazin derivatives, process for their preparation and their use as 5-dipoxygenase and cyclooxygenase inhibitors |
JPH09508906A (en) | 1994-02-14 | 1997-09-09 | メレル ファーマスーティカルズ インコーポレーテッド | Novel mercaptoacetylamide 1,3,4,5-tetrahydrobenzo [C] azepin-3-one disulfide derivatives useful as enkephalinase and ACE inhibitors |
GB9420557D0 (en) | 1994-10-12 | 1994-11-30 | Zeneca Ltd | Aromatic compounds |
DE4442050A1 (en) | 1994-11-25 | 1996-05-30 | Hoechst Ag | Heterospiro compounds and their use as electroluminescent materials |
US5650408A (en) | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
TW434240B (en) | 1995-06-20 | 2001-05-16 | Zeneca Ltd | Aromatic compounds, preparation thereof and pharmaceutical composition comprising same |
JP3895404B2 (en) | 1996-05-17 | 2007-03-22 | 興和株式会社 | Chalcone derivative and pharmaceutical containing the same |
CN1221417A (en) | 1996-07-26 | 1999-06-30 | 雷迪博士研究基金会 | Thiazolidinedione compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions thereof |
US6630496B1 (en) | 1996-08-26 | 2003-10-07 | Genetics Institute Llc | Inhibitors of phospholipase enzymes |
CA2264020A1 (en) | 1996-08-26 | 1998-03-05 | Jean Bemis | Inhibitors of phospholipase enzymes |
AU4136197A (en) | 1996-09-09 | 1998-03-26 | Kyowa Hakko Kogyo Co. Ltd. | Pyrrolocarbazole derivatives |
US6204221B1 (en) | 1996-11-12 | 2001-03-20 | Syngenta Crop Protection, Inc. | Herbicides |
US6043389A (en) | 1997-03-11 | 2000-03-28 | Mor Research Applications, Ltd. | Hydroxy and ether-containing oxyalkylene esters and uses thereof |
US5760232A (en) | 1997-06-16 | 1998-06-02 | Schering Corporation | Synthesis of intermediates useful in preparing bromo-substituted tricyclic compounds |
US6214817B1 (en) | 1997-06-20 | 2001-04-10 | Monsanto Company | Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity |
US6011042A (en) | 1997-10-10 | 2000-01-04 | Enzon, Inc. | Acyl polymeric derivatives of aromatic hydroxyl-containing compounds |
US6111107A (en) | 1997-11-20 | 2000-08-29 | Enzon, Inc. | High yield method for stereoselective acylation of tertiary alcohols |
DE19882892T1 (en) | 1997-12-12 | 2001-02-22 | Euro Celtique Sa | Preparation of 3-substituted adenines and imidazopyridines |
CA2322163A1 (en) | 1998-02-25 | 1999-09-02 | John Mckew | Inhibitors of phospholipase a2 |
CA2319493A1 (en) | 1998-03-18 | 1999-09-23 | Regine Bohacek | Heterocyclic signal transduction inhibitors, compositions containing them |
US6214879B1 (en) | 1998-03-24 | 2001-04-10 | Virginia Commonwealth University | Allosteric inhibitors of pyruvate kinase |
US6153655A (en) | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
GB9810860D0 (en) | 1998-05-20 | 1998-07-22 | Hoechst Schering Agrevo Gmbh | Substituted pyridine and pyrimidines, processes for their preparation and their use as pesticides |
WO1999062908A2 (en) | 1998-06-04 | 1999-12-09 | Abbott Laboratories | Cell adhesion-inhibiting antinflammatory compounds |
US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
GB9818627D0 (en) | 1998-08-26 | 1998-10-21 | Glaxo Group Ltd | Improvements in dva vaccination |
GB9823871D0 (en) | 1998-10-30 | 1998-12-23 | Pharmacia & Upjohn Spa | 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents |
US20030060425A1 (en) | 1998-11-24 | 2003-03-27 | Ahlem Clarence N. | Immune modulation method using steroid compounds |
KR100473966B1 (en) | 1998-12-14 | 2005-03-08 | 에프. 호프만-라 로슈 아게 | Phenylglycine derivatives |
CA2358955A1 (en) | 1998-12-31 | 2000-07-13 | Aventis Pharmaceuticals Inc. | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
US6544980B2 (en) | 1998-12-31 | 2003-04-08 | Aventis Pharmaceuticals Inc. | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
HUP0200705A3 (en) | 1999-03-31 | 2002-12-28 | Basf Ag | Herbicidal pyridine-2,3-dicarboxylic acid diamides and use thereof |
US6251927B1 (en) | 1999-04-20 | 2001-06-26 | Medinox, Inc. | Methods for treatment of sickle cell anemia |
WO2000069472A2 (en) | 1999-05-14 | 2000-11-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Enzyme-activated anti-tumor prodrug compounds |
US6184228B1 (en) | 1999-05-25 | 2001-02-06 | Anadys Pharmaceuticals, Inc. | Anti-sickling agents: selection methods and effective compounds |
EP1181296A1 (en) | 1999-06-03 | 2002-02-27 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
AUPQ105499A0 (en) | 1999-06-18 | 1999-07-08 | Biota Scientific Management Pty Ltd | Antiviral agents |
CN1210275C (en) | 1999-06-28 | 2005-07-13 | 詹森药业有限公司 | Respiratory syncytial virus replication inhibitors |
KR100694687B1 (en) | 1999-09-28 | 2007-03-13 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Quinuclidine compounds and drugs containing the same as the active ingredient |
CZ20021554A3 (en) | 1999-11-05 | 2002-10-16 | Emisphere Technologies, Inc. | Derivatives of a phenoxycarboxylic compound and preparations for delivering active component |
AUPQ407699A0 (en) | 1999-11-16 | 1999-12-09 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
AU2001230537A1 (en) | 2000-02-01 | 2001-08-14 | Daiichi Pharmaceutical Co., Ltd. | Pyridoxazine derivatives |
US6506755B2 (en) | 2000-02-03 | 2003-01-14 | Hoffmann-La Roche Inc. | Thiazolidinecarboxyl acids |
AUPQ585000A0 (en) | 2000-02-28 | 2000-03-16 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
WO2001070663A2 (en) | 2000-03-17 | 2001-09-27 | Corixa Corporation | Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors |
AUPQ841300A0 (en) | 2000-06-27 | 2000-07-20 | Fujisawa Pharmaceutical Co., Ltd. | New aminoalcohol derivatives |
PL205207B1 (en) | 2000-07-14 | 2010-03-31 | Hoffmann La Roche | N-oxides as nk1 receptor antagonist prodrugs of 4-phenyl-pyridine derivatives |
WO2002009723A2 (en) | 2000-08-01 | 2002-02-07 | Gmp Companies, Inc. | Ammonium salts of hemoglobin allosteric effectors, and uses thereof |
US6653313B2 (en) | 2000-08-10 | 2003-11-25 | Warner-Lambert Company Llc | 1,4-dihydropyridine compounds as bradykinin antagonists |
JP4272338B2 (en) | 2000-09-22 | 2009-06-03 | バイエル アクチェンゲゼルシャフト | Pyridine derivatives |
AUPR034000A0 (en) | 2000-09-25 | 2000-10-19 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
EP1335907B1 (en) | 2000-11-20 | 2010-06-09 | Biovitrum AB (publ) | Piperazinylpyrazine compounds as agonist or antagonist of serotonin 5ht-2 receptor |
JPWO2002051849A1 (en) | 2000-12-26 | 2004-04-22 | 第一製薬株式会社 | Cdk4 activity inhibitor |
ATE433964T1 (en) | 2000-12-28 | 2009-07-15 | Takeda Pharmaceutical | ALKANE ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
US20030022923A1 (en) | 2001-03-01 | 2003-01-30 | Medinox, Inc. | Methods for treatment of sickle cell anemia |
US6627646B2 (en) | 2001-07-17 | 2003-09-30 | Sepracor Inc. | Norastemizole polymorphs |
AU2002319677B8 (en) | 2001-07-23 | 2009-04-30 | Atwater Management Llc | Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods |
JP2003075970A (en) | 2001-08-31 | 2003-03-12 | Konica Corp | Silver halide color photographic sensitive material, color photographic sensitive material, image forming method for the same and method for creating digital image information |
KR100467313B1 (en) | 2001-11-22 | 2005-01-24 | 한국전자통신연구원 | Red organic electroluminescent compounds, method for synthesizing the same and electroluminescent devices |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
EP1465854A4 (en) | 2001-12-19 | 2005-06-08 | Atherogenics Inc | Chalcone derivatives and their use to treat diseases |
US20030190333A1 (en) | 2002-02-04 | 2003-10-09 | Corixa Corporation | Immunostimulant compositions comprising aminoalkyl glucosaminide phosphates and saponins |
WO2003088980A1 (en) | 2002-04-18 | 2003-10-30 | Embury Stephen H | Method and composition for preventing pain in sickle cell patients |
US6608076B1 (en) | 2002-05-16 | 2003-08-19 | Enzon, Inc. | Camptothecin derivatives and polymeric conjugates thereof |
GB0212785D0 (en) | 2002-05-31 | 2002-07-10 | Glaxo Group Ltd | Compounds |
KR20050071471A (en) | 2002-08-08 | 2005-07-07 | 스미스클라인 비참 코포레이션 | Thiophene compounds |
KR100942073B1 (en) | 2002-08-23 | 2010-02-12 | 기린 홀딩스 가부시키가이샤 | Compound Having TGF ? Inhibitory Activity and Medicinal Composition Containing the Same |
EP1541564A1 (en) | 2002-09-10 | 2005-06-15 | Takeda Pharmaceutical Company Limited | Five-membered heterocyclic compounds |
PT2179987E (en) | 2002-12-04 | 2013-03-11 | Univ Virginia Commonwealth | Use of heterocyclic carbaldehyde derivatives against sickle cell anemia |
AU2003303239A1 (en) | 2002-12-19 | 2004-07-14 | Atherogenics, Inc. | Process of making chalcone derivatives |
EP1577317A4 (en) | 2002-12-25 | 2007-05-09 | Kissei Pharmaceutical | Nitrogen-containing heterocycic derivatives, medicinal compositions containing the same and medicinal use thereof |
WO2004073675A1 (en) | 2003-02-24 | 2004-09-02 | Randolph Riemschneider | Cosmetic composition with a whitening effect, method for the production and use thereof |
US20040186077A1 (en) | 2003-03-17 | 2004-09-23 | Medicure International Inc. | Novel heteroaryl phosphonates as cardioprotective agents |
ZA200507752B (en) | 2003-03-28 | 2007-01-31 | Threshold Pharmaceuticals Inc | Compositions and methods for treating cancer |
CA2520259A1 (en) | 2003-04-11 | 2004-10-28 | Anormed Inc. | Cxcr4 chemokine receptor binding compounds |
JP2006527210A (en) | 2003-06-12 | 2006-11-30 | ノボ ノルディスク アクティーゼルスカブ | Pyridinyl carbamates as hormone-sensitive lipase inhibitors |
US7259164B2 (en) | 2003-08-11 | 2007-08-21 | Cgi Pharmaceuticals, Inc. | Certain substituted imidazo[1,2-a]pyrazines, as modulators of kinase activity |
US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
CN1875002B (en) | 2003-11-05 | 2011-08-03 | 霍夫曼-拉罗奇有限公司 | Phenyl derivatives as PPAR agonists |
AU2004289690A1 (en) | 2003-11-10 | 2005-05-26 | Schering Aktiengesellschaft | Benzylether amine compounds useful as CCR-5 antagonists |
EP1694328A4 (en) | 2003-12-02 | 2010-02-17 | Celgene Corp | Methods and compositions for the treatment and management of hemoglobinopathy and anemia |
US7378439B2 (en) | 2004-01-20 | 2008-05-27 | Usv, Ltd. | Process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride |
US20070155744A1 (en) | 2004-01-30 | 2007-07-05 | Istituto Di Ricerche Di Biologia Molecolare P, Angeletti S.P.A. | N-benzyl-3,4-dihyroxypyridine-2-carboxamide and n-benzyl-2,3-dihydroxypyridine-4- carboxamide compounds useful as hiv integrase inhibitors |
GB0403038D0 (en) | 2004-02-11 | 2004-03-17 | Novartis Ag | Organic compounds |
CA2557926A1 (en) | 2004-03-09 | 2005-09-22 | Monica Donghi | Hiv integrase inhibitors |
US20080132458A1 (en) | 2004-03-10 | 2008-06-05 | Threshold Pharmaceuticals, Inc. | Hypoxia-Activated Anti-Cancer Agents |
DE102004015226B3 (en) | 2004-03-24 | 2005-08-25 | Siemens Ag | Plasma cleaning method suitable for interior surfaces of e.g. bulbs for discharge lamps, forms back pressure and ignites plasma only inside bulb |
US20070293698A1 (en) | 2004-04-22 | 2007-12-20 | Allos Therapeutics, Inc. | Compositions of Allosteric Hemoglobin Modifiers and Methods of Making the Same |
WO2006003923A1 (en) | 2004-06-30 | 2006-01-12 | Sankyo Company, Limited | Substituted benzene compound |
TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
GB0420722D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
EP1817288A4 (en) | 2004-10-28 | 2009-08-26 | Medicure Int Inc | Dual antiplatelet/anticoagulant pyridoxine analogs |
WO2006065204A1 (en) | 2004-12-14 | 2006-06-22 | Astrazeneca Ab | Substituted aminopyridines and uses thereof |
WO2006088173A1 (en) | 2005-02-21 | 2006-08-24 | Shionogi & Co., Ltd. | Bicyclic carbamoylpyridone derivative having hiv integrase inhibiting activity |
MX2007011466A (en) | 2005-03-19 | 2008-01-16 | Amorepacific Corp | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same. |
WO2006106711A1 (en) | 2005-03-30 | 2006-10-12 | Eisai R & D Management Co., Ltd. | Antifungal agent containing pyridine derivative |
GB0506677D0 (en) | 2005-04-01 | 2005-05-11 | Btg Int Ltd | Iron modulators |
PL3284520T3 (en) | 2005-04-28 | 2020-01-31 | Viiv Healthcare Company | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
DE102005025989A1 (en) | 2005-06-07 | 2007-01-11 | Bayer Cropscience Ag | carboxamides |
JP2006342115A (en) | 2005-06-10 | 2006-12-21 | Shionogi & Co Ltd | Polycyclic compound having hiv integrase inhibition activity |
AU2006264649A1 (en) | 2005-06-30 | 2007-01-11 | Prosidion Limited | GPCR agonists |
CN100562514C (en) | 2005-07-22 | 2009-11-25 | 中国科学院上海药物研究所 | Substituted propion amide derivatives, Preparation Method And The Use |
GB0516270D0 (en) | 2005-08-08 | 2005-09-14 | Glaxo Group Ltd | Novel compounds |
PL1945622T3 (en) | 2005-10-11 | 2012-06-29 | Univ Pittsburgh Commonwealth Sys Higher Education | Isotopically-labeled benzofuran compounds as imagingagents for amyloidogenic proteins |
EP1950212B1 (en) | 2005-10-27 | 2016-02-24 | Shionogi Co., Ltd. | Polycyclic carbamoylpyridone derivative having inhibitory activity on hiv integrase |
EP1948614A2 (en) | 2005-11-18 | 2008-07-30 | Takeda San Diego, Inc. | Glucokinase activators |
WO2007084914A2 (en) | 2006-01-17 | 2007-07-26 | Neurocrine Biosciences, Inc. | Phenoxy-substituted pyrimidines as adenosine receptor antagonists |
WO2007095495A2 (en) | 2006-02-13 | 2007-08-23 | Pharmacopeia, Inc. | Benzodiazepine gcnf modulators for stem cell modulation |
RU2318818C1 (en) | 2006-04-12 | 2008-03-10 | Общество С Ограниченной Ответственностью "Исследовательский Институт Химического Разнообразия" | Azaheterocycles, combinatory library, focused library, pharmaceutical composition and method for preparing (variants) |
GB0614586D0 (en) | 2006-07-22 | 2006-08-30 | Pliva Istrazivacki Inst D O O | Pharmaceutical Formulation |
CN101113148A (en) | 2006-07-26 | 2008-01-30 | 中国海洋大学 | Dioxygen piperazidine compounds and preparation method and usage thereof |
CA2658925C (en) | 2006-07-27 | 2015-07-14 | Amorepacific Corporation | Novel sulfonylamino acrylamide derivatives, isomer thereof,or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same |
TW200817424A (en) | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
TWI389895B (en) | 2006-08-21 | 2013-03-21 | Infinity Discovery Inc | Compounds and methods for inhibiting the interaction of bcl proteins with binding partners |
EP2061749B1 (en) | 2006-09-03 | 2018-02-21 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate |
AU2007303846B2 (en) | 2006-10-04 | 2011-03-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as calcium receptor antagonists |
CA2667007A1 (en) | 2006-10-23 | 2008-05-02 | Merck & Co., Inc. | 2-[1-phenyl-5-hydroxy or methoxy-4alpha-methyl-hexahydrocyclopenta[f]indazol-5-yl]ethyl phenyl derivatives as glucocorticoid receptor ligands |
FR2909379B1 (en) | 2006-11-30 | 2009-01-16 | Servier Lab | NOVEL HETEROCYCLIC DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME. |
TW200835687A (en) | 2006-11-30 | 2008-09-01 | R Tech Ueno Ltd | Thiazole derivatives and their use as VAP-1 inhibitor |
CA2670984A1 (en) | 2006-11-30 | 2008-06-05 | Tokyo Institute Of Technology | Novel curcumin derivative |
RU2487119C2 (en) | 2007-02-22 | 2013-07-10 | Зингента Партисипейшнс Аг | Iminopyrimidine derivatives and use thereof as microbiocides |
TWI407960B (en) | 2007-03-23 | 2013-09-11 | Jerini Ag | Small molecule bradykinin b2 receptor modulators |
WO2008143264A1 (en) | 2007-05-22 | 2008-11-27 | Sumitomo Chemical Company, Limited | Method for producing benzaldehyde compound |
WO2009001214A2 (en) | 2007-06-28 | 2008-12-31 | Pfizer Products Inc. | Thieno[2,3-d]pyrimidin-4(3h)-one, isoxazolo[5,4-d]pyrimidin-4(5h)-one and isothiazolo[5,4-d]pyrimidin-4(5h)-one derivatives as calcium receptor antagonists |
WO2009011850A2 (en) | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Novel therapeutic compounds |
KR101158191B1 (en) | 2007-07-17 | 2012-06-19 | 에프. 호프만-라 로슈 아게 | Inhibitors of 11b-hydroxysteroid dehydrogenase |
PE20090506A1 (en) | 2007-07-26 | 2009-05-28 | Novartis Ag | DERIVATIVES OF IMIDAZO- [1,2-b] -PYRIDAZINE AS INHIBITORS OF ALK5 AND / OR ALK4 |
TW200918521A (en) * | 2007-08-31 | 2009-05-01 | Astrazeneca Ab | Heterocyclic amides and methods of use thereof |
JP5456681B2 (en) | 2007-10-17 | 2014-04-02 | ノバルティス アーゲー | Imidazo [1,2-a] pyridine derivatives useful as ALK inhibitors |
DK2767536T3 (en) | 2007-12-04 | 2015-10-19 | Hoffmann La Roche | Isoxazolo-pyridine derivatives |
US7776875B2 (en) | 2007-12-19 | 2010-08-17 | Hoffman-La Roche Inc. | Spiroindolinone derivatives |
JP2009203230A (en) | 2008-01-31 | 2009-09-10 | Daiichi Sankyo Co Ltd | Pharmaceutical composition containing benzyl phenyl glucopyranoside derivative |
EP2272817A4 (en) | 2008-04-11 | 2011-12-14 | Inst Med Molecular Design Inc | Pai-1 inhibitor |
US8633245B2 (en) | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
JP2011136906A (en) | 2008-04-18 | 2011-07-14 | Otsuka Pharmaceut Co Ltd | Heterocyclic compound |
US8119647B2 (en) | 2008-04-23 | 2012-02-21 | Glenmark Pharmaceuticals S.A. | Fused pyrimidineone compounds as TRPV3 modulators |
EP2271341B1 (en) | 2008-05-08 | 2016-08-17 | Nova Southeastern University | Specific inhibitors for vascular endothelial growth factor receptors |
US8742123B2 (en) | 2008-06-04 | 2014-06-03 | Taimed Biologics, Inc. | HIV integrase inhibitors from pyridoxine |
DE102008027574A1 (en) | 2008-06-10 | 2009-12-17 | Merck Patent Gmbh | New pyrrolidine derivatives as MetAP-2 inhibitors |
JP5314330B2 (en) | 2008-06-16 | 2013-10-16 | 住友化学株式会社 | Process for producing 2- (aryloxymethyl) benzaldehyde and its intermediate |
GB0811451D0 (en) | 2008-06-20 | 2008-07-30 | Syngenta Participations Ag | Novel microbiocides |
AR073304A1 (en) | 2008-09-22 | 2010-10-28 | Jerini Ag | MODULATORS OF THE BRADIQUININE B2 RECEPTOR OF SMALL MOLECULA |
AU2009314299A1 (en) | 2008-11-12 | 2010-05-20 | Merck Sharp & Dohme Corp. | Inhibitors of fatty acid binding protein (FABP) |
TW201033201A (en) | 2009-02-19 | 2010-09-16 | Hoffmann La Roche | Isoxazole-isoxazole and isoxazole-isothiazole derivatives |
DK3222277T3 (en) | 2009-03-31 | 2020-05-11 | Ligand Pharm Inc | Biphenylsulfonamide endothelin and angiotensin II receptor antagonist for the treatment of glomerulosclerosis and IgA-induced nephropathy |
WO2010129055A1 (en) | 2009-05-08 | 2010-11-11 | Tetraphase Pharmaceuticals, Inc. | 8-aza tetracycline compounds |
US8486965B2 (en) | 2009-08-26 | 2013-07-16 | Takeda Pharmaceutical Company Limited | Pyrrolo[2,3-b]pyridine derivative and use thereof for treatment of cancer |
EP2474540A4 (en) | 2009-08-31 | 2013-03-13 | Nippon Chemiphar Co | Gpr119 agonist |
EP2480533A1 (en) | 2009-09-21 | 2012-08-01 | F. Hoffmann-La Roche AG | Heterocyclic antiviral compounds |
FI2498756T4 (en) | 2009-11-09 | 2023-03-22 | Tablet formulations of neratinib maleate | |
TW201139406A (en) | 2010-01-14 | 2011-11-16 | Glaxo Group Ltd | Voltage-gated sodium channel blockers |
KR101698153B1 (en) | 2010-04-26 | 2017-01-23 | 광주과학기술원 | Novel pyridine carboxylic acid compound as a P2X1 and P2X3 receptor antagonist, the preparation method thereof and a composition containing the same |
CN102232949A (en) | 2010-04-27 | 2011-11-09 | 孙远 | Drug dissolution increasing composition and preparation method thereof |
TWI535442B (en) * | 2010-05-10 | 2016-06-01 | Kyowa Hakko Kirin Co Ltd | A nitrogen-containing heterocyclic compound having an action of inhibiting the production of canine erythritine |
US20120122928A1 (en) | 2010-08-11 | 2012-05-17 | Bayer Cropscience Ag | Heteroarylpiperidine and -Piperazine Derivatives as Fungicides |
CN102116772B (en) | 2010-09-28 | 2013-08-28 | 上海大学 | Method for screening dihydrochalcone compound |
SG10201602311XA (en) | 2010-12-27 | 2016-04-28 | Takeda Pharmaceutical | Orally disintegrating tablet |
EP2694514A2 (en) | 2011-04-06 | 2014-02-12 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
US9399635B2 (en) | 2011-04-11 | 2016-07-26 | Green Tech Co., Ltd. | Pyrazole derivative |
CN102952062B (en) | 2011-08-12 | 2016-06-08 | 中国医学科学院医药生物技术研究所 | Replace benzo-heterocycle compound and its preparation method and application |
KR20140062472A (en) | 2011-09-15 | 2014-05-23 | 데메알엑스, 인크. | Noribogaine salt ansolvates |
WO2013052803A2 (en) | 2011-10-07 | 2013-04-11 | Radiorx, Inc. | Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products |
US9012450B2 (en) | 2011-12-28 | 2015-04-21 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
AP2014007805A0 (en) | 2011-12-28 | 2014-07-31 | Cytokinetics Inc The Regents Of The University Of California | Substituted benzaldehyde compounds and methods fortheir use in increasing tissue oxygenation |
JP6237646B2 (en) | 2012-12-27 | 2017-11-29 | 住友化学株式会社 | Tetrazolinone compounds and uses thereof |
FR3003412B1 (en) * | 2013-03-14 | 2016-12-09 | Valeo Equip Electr Moteur | ELECTRIC MACHINE ROTOR PROVIDED WITH AT LEAST ONE WELDING CHUNK HOLDING FREIGHT AND CORRESPONDING ELECTRIC MACHINE |
CA2902874C (en) | 2013-03-15 | 2021-04-20 | Global Blood Therapeutics, Inc. | Substituted pyridinyl-6-methoxy-benzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin |
EP2970308B1 (en) | 2013-03-15 | 2021-07-14 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
WO2014150256A1 (en) | 2013-03-15 | 2014-09-25 | Global Blood Therapeutics, Inc. | Compositions and methods for the modulation of hemoglobin (s) |
SG10201802911RA (en) | 2013-03-15 | 2018-05-30 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin |
US20140271591A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Compositions and methods for the modulation of hemoglobin (s) |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
SG11201507351PA (en) | 2013-03-15 | 2015-10-29 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin |
US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
US20150057251A1 (en) | 2013-08-26 | 2015-02-26 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin |
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US20140274961A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
MX2015011769A (en) | 2013-03-15 | 2016-06-02 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin. |
WO2015031284A1 (en) | 2013-08-26 | 2015-03-05 | Global Blood Therapeutics, Inc. | Formulations comprising wetting agents and compounds for the modulation of hemoglobin (s) |
US20160207904A1 (en) | 2013-08-27 | 2016-07-21 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
WO2015031285A1 (en) | 2013-08-27 | 2015-03-05 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
EA201992707A1 (en) | 2013-11-18 | 2020-06-30 | Глобал Блад Терапьютикс, Инк. | COMPOUNDS AND THEIR APPLICATIONS FOR HEMOGLOBIN MODULATION |
US20150141465A1 (en) | 2013-11-18 | 2015-05-21 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9248199B2 (en) | 2014-01-29 | 2016-02-02 | Global Blood Therapeutics, Inc. | 1:1 adducts of sickle hemoglobin |
PT3102208T (en) | 2014-02-07 | 2021-04-05 | Global Blood Therapeutics Inc | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
MA41841A (en) | 2015-03-30 | 2018-02-06 | Global Blood Therapeutics Inc | ALDEHYDE COMPOUNDS FOR THE TREATMENT OF PULMONARY FIBROSIS, HYPOXIA, AND AUTOIMMUNE AND CONNECTIVE TISSUE DISEASES |
BR112018011272A2 (en) | 2015-12-04 | 2018-11-21 | Global Blood Therapeutics Inc | 2-hydroxy-6 - ((2- (1-isopropyl-1h-pyrazol-5-yl) pyridin-3-yl) methoxy) benzaldehyde dosage regimens |
TWI752307B (en) | 2016-05-12 | 2022-01-11 | 美商全球血液治療公司 | Novel compound and method of preparing compound |
TWI778983B (en) | 2016-10-12 | 2022-10-01 | 美商全球血液治療公司 | Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
-
2012
- 2012-12-28 US US13/730,730 patent/US9012450B2/en active Active
- 2012-12-28 WO PCT/US2012/072183 patent/WO2013102145A1/en active Application Filing
- 2012-12-28 ES ES12862096T patent/ES2790358T3/en active Active
- 2012-12-28 EP EP12862096.0A patent/EP2797597B1/en active Active
-
2015
- 2015-03-18 US US14/662,145 patent/US20150344483A1/en not_active Abandoned
- 2015-04-29 HK HK15104172.5A patent/HK1203412A1/en unknown
-
2016
- 2016-12-27 US US15/391,669 patent/US20170107199A1/en not_active Abandoned
-
2018
- 2018-01-08 US US15/864,433 patent/US10377741B2/en active Active
-
2019
- 2019-07-23 US US16/519,552 patent/US10822326B2/en active Active
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Publication number | Publication date |
---|---|
WO2013102145A1 (en) | 2013-07-04 |
US20200190058A1 (en) | 2020-06-18 |
HK1203412A1 (en) | 2015-10-30 |
EP2797597A4 (en) | 2015-06-24 |
US10822326B2 (en) | 2020-11-03 |
US20170107199A1 (en) | 2017-04-20 |
US9012450B2 (en) | 2015-04-21 |
ES2790358T3 (en) | 2020-10-27 |
US10377741B2 (en) | 2019-08-13 |
US20180354929A1 (en) | 2018-12-13 |
EP2797597A1 (en) | 2014-11-05 |
US20130190316A1 (en) | 2013-07-25 |
US20150344483A1 (en) | 2015-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2797597B1 (en) | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation | |
AU2021232806B2 (en) | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation | |
OA19779A (en) | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20140718 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAX | Request for extension of the european patent (deleted) | ||
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 487/04 20060101ALI20150430BHEP Ipc: C07D 403/14 20060101ALI20150430BHEP Ipc: C07D 401/14 20060101ALI20150430BHEP Ipc: C07D 401/12 20060101ALI20150430BHEP Ipc: C07D 471/14 20060101ALI20150430BHEP Ipc: A61K 31/44 20060101AFI20150430BHEP |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61K 31/44 20060101AFI20150504BHEP Ipc: C07D 401/14 20060101ALI20150504BHEP Ipc: C07D 403/14 20060101ALI20150504BHEP Ipc: C07D 487/04 20060101ALI20150504BHEP Ipc: C07D 471/14 20060101ALI20150504BHEP Ipc: C07D 401/12 20060101ALI20150504BHEP |
|
RA4 | Supplementary search report drawn up and despatched (corrected) |
Effective date: 20150528 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 401/14 20060101ALI20150521BHEP Ipc: C07D 403/14 20060101ALI20150521BHEP Ipc: A61K 31/44 20060101AFI20150521BHEP Ipc: C07D 471/14 20060101ALI20150521BHEP Ipc: C07D 487/04 20060101ALI20150521BHEP Ipc: C07D 401/12 20060101ALI20150521BHEP |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1203412 Country of ref document: HK |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20170407 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA Owner name: CYTOKINETICS, INC. Owner name: GLOBAL BLOOD THERAPEUTICS, INC. |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA Owner name: GLOBAL BLOOD THERAPEUTICS, INC. |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20181116 |
|
GRAJ | Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted |
Free format text: ORIGINAL CODE: EPIDOSDIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTC | Intention to grant announced (deleted) | ||
INTG | Intention to grant announced |
Effective date: 20190410 |
|
GRAJ | Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted |
Free format text: ORIGINAL CODE: EPIDOSDIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTC | Intention to grant announced (deleted) | ||
INTG | Intention to grant announced |
Effective date: 20190909 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: VENI GMBH, CH Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602012068146 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1236805 Country of ref document: AT Kind code of ref document: T Effective date: 20200315 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PCOW Free format text: NEW ADDRESS: 1111 FRANKLIN STREET, 12TH FLOOR, OAKLAND, CA 94607 (US) $ GLOBAL BLOOD THERAPEUTICS, INC., 181 OYSTER POINT BLVD., SOUTH SAN FRANCISCO, CA 94080 (US) |
|
RAP2 | Party data changed (patent owner data changed or rights of a patent transferred) |
Owner name: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA Owner name: GLOBAL BLOOD THERAPEUTICS, INC. |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200526 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200626 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200527 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200526 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2790358 Country of ref document: ES Kind code of ref document: T3 Effective date: 20201027 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200719 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 1236805 Country of ref document: AT Kind code of ref document: T Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602012068146 Country of ref document: DE |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
26N | No opposition filed |
Effective date: 20201127 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1203412 Country of ref document: HK |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20201231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20201228 Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20201228 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200226 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20201231 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230502 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20231108 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20231215 Year of fee payment: 12 Ref country code: FR Payment date: 20231108 Year of fee payment: 12 Ref country code: DE Payment date: 20231108 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20240109 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20240101 Year of fee payment: 12 |